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JAMA Oncology May 2024To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
To date, no meta-analyses have comprehensively assessed the association of neoadjuvant chemoimmunotherapy with clinical outcomes in non-small cell lung cancer (NSCLC) in randomized and nonrandomized settings. In addition, there exists controversy concerning the efficacy of neoadjuvant chemoimmunotherapy for patients with NSCLC with programmed cell death 1 ligand 1 (PD-L1) levels less than 1%.
OBJECTIVE
To compare neoadjuvant chemoimmunotherapy with chemotherapy by adverse events and surgical, pathological, and efficacy outcomes using recently published randomized clinical trials and nonrandomized trials.
DATA SOURCES
MEDLINE and Embase were systematically searched from January 1, 2013, to October 25, 2023, for all clinical trials of neoadjuvant chemoimmunotherapy and chemotherapy that included at least 10 patients.
STUDY SELECTION
Observational studies and trials reporting the use of neoadjuvant radiotherapy, including chemoradiotherapy, molecular targeted therapy, or immunotherapy monotherapy, were excluded.
MAIN OUTCOMES AND MEASURES
Surgical, pathological, and efficacy end points and adverse events were pooled using a random-effects meta-analysis.
RESULTS
Among 43 eligible trials comprising 5431 patients (4020 males [74.0%]; median age range, 55-70 years), there were 8 randomized clinical trials with 3387 patients. For randomized clinical trials, pooled overall survival (hazard ratio, 0.65; 95% CI, 0.54-0.79; I2 = 0%), event-free survival (hazard ratio, 0.59; 95% CI, 0.52-0.67; I2 = 14.9%), major pathological response (risk ratio, 3.42; 95% CI, 2.83-4.15; I2 = 31.2%), and complete pathological response (risk ratio, 5.52; 95% CI, 4.25-7.15; I2 = 27.4%) favored neoadjuvant chemoimmunotherapy over neoadjuvant chemotherapy. For patients with baseline tumor PD-L1 levels less than 1%, there was a significant benefit in event-free survival for neoadjuvant chemoimmunotherapy compared with chemotherapy (hazard ratio, 0.74; 95% CI, 0.62-0.89; I2 = 0%).
CONCLUSION AND RELEVANCE
This study found that neoadjuvant chemoimmunotherapy was superior to neoadjuvant chemotherapy across surgical, pathological, and efficacy outcomes. These findings suggest that patients with resectable NSCLC with tumor PD-L1 levels less than 1% may have an event-free survival benefit with neoadjuvant chemoimmunotherapy.
Topics: Aged; Humans; Middle Aged; Carcinoma, Non-Small-Cell Lung; Immunotherapy; Lung Neoplasms; Neoadjuvant Therapy; Treatment Outcome
PubMed: 38512301
DOI: 10.1001/jamaoncol.2024.0057 -
The Cochrane Database of Systematic... Oct 2017Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'.
OBJECTIVES
To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults.
METHODS
We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework.
MAIN RESULTS
We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity.
AUTHORS' CONCLUSIONS
A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.
Topics: Adult; Analgesics, Opioid; Chronic Pain; Humans; Patient Dropouts; Randomized Controlled Trials as Topic; Review Literature as Topic; Time Factors
PubMed: 29084357
DOI: 10.1002/14651858.CD012509.pub2 -
Clinical Gastroenterology and... Jun 2023Multiple drugs have been used to treat gastroparesis symptoms, yet their therapeutic benefits are poorly understood partly due to lack of insight into response and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Multiple drugs have been used to treat gastroparesis symptoms, yet their therapeutic benefits are poorly understood partly due to lack of insight into response and adverse event rates with placebo in randomized controlled trials (RCTs). We evaluated these issues systematically in drug trials for gastroparesis.
METHODS
We searched the medical literature through August 2, 2022 to identify RCTs comparing active drug with placebo in patients with gastroparesis. We assessed placebo response rates according to at least one of the following endpoints: improvement according to a composite outcome, nausea, vomiting, abdominal pain, bloating, or fullness, as well as total adverse events, and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses with dropouts assumed to be treatment failures. We pooled placebo response and adverse event rates using a random effects model and expressed as proportions with 95% confidence intervals (CIs).
RESULTS
Thirty-five studies were eligible. Among 23 trials reporting a composite endpoint of improvement, the pooled placebo response rate was 29.3% (95% CI, 23.7%-35.2%). Pooled placebo response rates were higher in idiopathic compared with diabetic gastroparesis (34.2% vs 28.1%), among trials that did not use validated symptom questionnaires (31.2% vs 27.4%), and in RCTs of shorter duration (<4 weeks, 32.6% vs ≥9 weeks, 23.2%). Adverse events occurred in 33.8% (95% CI, 26.4%-41.8%) of patients with placebo, in 27 trials, and were less common in idiopathic compared with diabetic gastroparesis (17.9% vs 43.4%), trials of shorter duration (<4 weeks, 33.7% vs ≥9 weeks, 40.7%), and trials with lower randomization ratios of active drug to placebo (1:1, 26.7% vs 3:1, 50.5%).
CONCLUSIONS
This meta-analysis assessed placebo response and adverse event rates in gastroparesis. To accurately assess therapeutic gain, future trials should be a minimum of 8 weeks duration, use validated questionnaires, and distinguish gastroparesis subtypes.
Topics: Humans; Gastroparesis; Vomiting; Nausea
PubMed: 36270614
DOI: 10.1016/j.cgh.2022.09.033 -
Frontiers in Pharmacology 2023We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among...
We performed a systematic review and network meta-analysis evaluating the safety and efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) among dialysis chronic kidney disease patients. Safety was evaluated with any adverse events (AEs), serious adverse events (SAEs), and 12 common events. Efficacy was mainly analyzed with hemoglobin response. All reported results were summarized using mean difference and risk ratio (RR) with 95% confidence interval (CI). Publication bias was assessed through funnel plots. Twenty trials (19 studies) with 14,947 participants were included, comparing six HIF-PHIs with erythropoiesis-stimulating agents (ESAs). No significant differences were indicated in overall AEs and SAEs between each HIF-PHI and ESA. The occurrence of gastrointestinal disorder was higher in enarodustat and roxadustat than in ESAs (RR: 6.92, 95% CI: 1.52-31.40, = 0.01; RR: 1.30, 95% CI: 1.04-1.61, = 0.02). The occurrence of hypertension was lower in vadadustat than in ESAs (RR: 0.81, 95% CI: 0.69-0.96, = 0.01). The occurrence of vascular-access complications was higher in roxadustat (RR: 1.15, 95% CI: 1.04-1.27, <0.01) and lower in daprodustat (RR: 0.78, 95% CI: 0.66-0.92, <0.01) than in ESAs. In the risk of the other nine events, including cardiovascular events, no significant differences were observed between HIF-PHIs and ESAs. For hemoglobin response, network meta-analysis showed that compared with ESAs, significant increases were shown in roxadustat (RR: 1.04, 95% CI: 1.01-1.07, <0.01) and desidustat (RR: 1.22, 95% CI: 1.01-1.48, = 0.04), whereas noticeable reductions were indicated in vadadustat (RR: 0.88, 95% CI: 0.82-0.94, <0.01) and molidustat (RR: 0.83, 95% CI: 0.70-0.98, = 0.02). There was no significant difference between daprodustat and ESAs (RR: 0.97, 95% CI: 0.89-1.06, = 0.47). Although HIF-PHIs did not show significant differences from ESAs in terms of overall AEs and SAEs, statistical differences in gastrointestinal disorder, hypertension, and vascular-access complications were observed between HIF-PHIs, which deserved to be noted in clinical decision making. This study is registered with PROSPERO (registration number CRD42022312252).
PubMed: 37292157
DOI: 10.3389/fphar.2023.1163908 -
The Journal of Pain Nov 2016Thorough assessment and reporting of adverse events (AEs) facilitates a detailed understanding of a treatment's risk-benefit profile. Although the Consolidated Standards... (Review)
Review
UNLABELLED
Thorough assessment and reporting of adverse events (AEs) facilitates a detailed understanding of a treatment's risk-benefit profile. Although the Consolidated Standards of Reporting Trials (CONSORT) 2004 statement provides recommendations regarding AE reporting, adherence to these standards is often inadequate. We investigated AE reporting in clinical trials of intravenous and invasive pain treatments published in 6 major anesthesiology and pain journals between 2000 to 2003 and 2006 to 2012. We examined whether AE reporting improved after publication of the 2004 CONSORT recommendations and also comprehensively reviewed AE assessment using the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting recommendations. No improvement was found overall in CONSORT harms reporting scores from pre- to postpublication of the CONSORT recommendations, with only 5 of 10 fulfilled on average. AE reporting assessed using the ACTTION coding manual was generally inadequate, and 8% of articles failed to report any AE information at all. Anesthesiology and pain journals were similar in AE reporting quality, although industry-sponsored trials reported more AE information than nonindustry sponsored trials. Improvement is needed in AE reporting in analgesic clinical trials. The CONSORT checklist and ACTTION AE recommendations can assist investigators and editors in improving clinical trial transparency and quality.
PERSPECTIVE
This systematic review of AE reporting in intravenous and invasive pain treatment trials shows that little improvement has been made since the 2004 CONSORT harms reporting guidelines. Better assessment and reporting of treatment AEs is necessary to understand the full clinical effect of intravenous and invasive treatments.
Topics: Administration, Intravenous; Analgesics; Clinical Trials as Topic; Databases, Bibliographic; Humans; Pain
PubMed: 27522950
DOI: 10.1016/j.jpain.2016.07.006 -
Toxicology Reports 2023Cannabis is the most used illicit drug in the world. Global trends of decriminalization and legalization of cannabis lead to various forms of cannabis use and bring...
BACKGROUND
Cannabis is the most used illicit drug in the world. Global trends of decriminalization and legalization of cannabis lead to various forms of cannabis use and bring great concerns over adverse events, particularly in the cardiovascular (CV) system. To date, the association between cannabis and adverse CV events is still controversial.
PURPOSE
We aim to conduct a systematic review and meta-analysis to assess the adverse CV events from cannabis use.
PATIENTS AND METHODS
A systematic search for publications describing the adverse CV events of cannabis use, including acute myocardial infarction (MI) and stroke, was performed via PubMed, Scopus, and Cochrane Library databases. Data on effect estimates in individual studies were extracted and combined via random-effects meta-analysis using the DerSimonian and Laird method, a generic inverse-variance strategy.
RESULTS
Twenty studies with a total of 183,410,651 patients were included. The proportion of males was 23.7%. The median age and follow-up time were 42.4 years old (IQR: 37.4, 50.0) and 6.2 years (IQR: 1.7, 27.7), respectively. The prevalence of cannabis use was 1.9%. Cannabis use was not significantly associated with acute MI (pooled odds ratio (OR): 1.29; 95%CI: 0.80, 2.08), stroke (pooled OR 1.35; 95%CI: 0.74, 2.47), and adverse CV events (pooled OR: 1.47; 95%CI: 0.98, 2.20).
CONCLUSION
The risk of adverse CV events including acute MI and stroke does not exhibit a significant increase with cannabis exposure. However, caution should be exercised when interpreting the findings due to the heterogeneity of the studies.
PubMed: 37168078
DOI: 10.1016/j.toxrep.2023.04.011 -
Journal of Psychiatric Research May 2024Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good... (Review)
Review
Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good Clinical Practice and the Harms Extension of the CONSORT (Consolidated Standards of Reporting Trials) Statement, we identified how adverse events are measured, assessed, and reported in studies evaluating neuromodulation for the treatment of mental and neurodevelopmental disorders among children and adolescents. A systematic literature review identified 56 experimental and quasi-experimental studies evaluating transcranial magnetic stimulation (TMS), transcranial alternating (tACS) or direct (tDCS) current stimulation, transcranial pulse stimulation (TPS), and vagus or trigeminal nerve stimulation (VNS or TNS). For 22 studies (39%), the types of adverse events to be monitored were identified, and for 31 studies (55%), methods for collecting adverse event data were described. Methods for assessing adverse events were less commonly described with 23 studies (41%) having details on assessing event severity, and 11 studies (20%) having details on assessing event causality. Among 31 studies with reported results, headache, skin irritation, and general pain or discomfort were the most reported across studies. Seizure, untoward medical occurrences, and intracranial bleeding, edema, or other intracranial pathology were considered serious events, but these events were not reported as occurring in any results-based papers. Taken together, the findings from this review indicate that most studies of pediatric neuromodulatory interventions did not include descriptions of adverse event monitoring and evaluation. Comprehensive event monitoring and reporting across studies can significantly augment the current knowledge base.
PubMed: 38761518
DOI: 10.1016/j.jpsychires.2024.05.035 -
Global Spine Journal Dec 2015Study Design Systematic review. Objectives (1) To compare the quality of adverse event (AE) methodology and reporting among randomized trials comparing lumbar fusion... (Review)
Review
Study Design Systematic review. Objectives (1) To compare the quality of adverse event (AE) methodology and reporting among randomized trials comparing lumbar fusion with lumbar total disk replacement (TDR) using established AE reporting systems; (2) to compare the AEs and reoperations of lumbar spinal fusion with those from lumbar TDR; (3) to make recommendations on how to report AEs in randomized controlled trials (RCTs) so that surgeons and patients have more-detailed and comprehensive information when making treatment decisions. Methods A systematic search of PubMed, the Cochrane collaboration database, and the National Guideline Clearinghouse through May 2015 was conducted. Randomized controlled trials with at least 2 years of follow-up comparing lumbar artificial disk replacement with lumbar fusion were included. Patients were required to have axial or mechanical low back pain of ≥3 months' duration due to degenerative joint disease defined as degenerative disk disease, facet joint disease, or spondylosis. Outcomes included the quality of AE acquisition methodology and results reporting, and AEs were defined as those secondary to the procedure and reoperations. Individual and pooled relative risks and their 95% confidence intervals comparing lumbar TDR with fusion were calculated. Results RCTs demonstrated a generally poor description of methods for assessing AEs. There was a consistent lack of clear definition or grading for these events. Furthermore, there was a high degree of variation in reporting of surgery-related AEs. Most studies lacked adequate reporting of the timing of AEs, and there were no clear distinctions between acute or chronic AEs. Meta-analysis of the pooled data demonstrated a twofold increased risk of AEs in patients having lumbar fusion compared with patients having lumbar TDR at 2-year follow-up, and this relative risk was maintained at 5 years. Furthermore, the pooled data demonstrated a 1.7 times greater relative risk of reoperation in the fusion group compared with lumbar TDR, although this risk decreased to 1.1 at 5-year follow-up. However, given the lack of quality and consistency in the methods of recording and reporting of AEs, we are unable to make a clear recommendation of one treatment over the other. Conclusions Based on the currently available literature, lumbar TDR appears to be comparable in safety to lumbar fusion. However, due to lack of consistency in reporting of AEs, it is difficult to make conclusions regarding the true safety profile of lumbar TDR. Standardization in AE reporting will significantly improve the reliability of the current literature.
PubMed: 26682099
DOI: 10.1055/s-0035-1567835 -
Current Neuropharmacology 2023Compelling evidence from preclinical and clinical studies supports the therapeutic role of cannabidiol (CBD) in several medical disorders. We reviewed the scientific...
BACKGROUND
Compelling evidence from preclinical and clinical studies supports the therapeutic role of cannabidiol (CBD) in several medical disorders. We reviewed the scientific evidence on CBD-related toxicity and adverse events (AEs) in 2019, at the beginning of the spike in clinical studies involving CBD. However, CBD safety remained uncertain.
OBJECTIVE
With the benefit of hindsight, we aimed to provide an update on CBD-related toxicity and AEs in humans.
METHODS
A systematic literature search was conducted following PRISMA guidelines. PubMed, Cochrane, and Embase were accessed in October 2022 to identify clinical studies mentioning CBDrelated toxicity/AEs from February 2019 to September 2022. Study design, population characteristics, CBD doses, treatment duration, co-medications, and AEs were compiled.
RESULTS
A total of 51 reports were included. Most studies investigated CBD efficacy and safety in neurological conditions, such as treatment-resistant epilepsies, although a growing number of studies are focusing on specific psychopathological conditions, such as substance use disorders, chronic psychosis, and anxiety. Most studies report mild or moderate severity of AEs. The most common AEs are diarrhea, somnolence, sedation, and upper respiratory disturbances. Few serious AEs have been reported, especially when CBD is co-administered with other classes of drugs, such as clobazam and valproate.
CONCLUSION
Clinical data suggest that CBD is well tolerated and associated with few serious AEs at therapeutic doses both in children and adults. However, interactions with other medications should be monitored carefully. Additional data are needed to investigate CBD's long-term efficacy and safety, and CBD use in medical conditions other than epilepsy syndromes.
Topics: Child; Adult; Humans; Cannabidiol; Epilepsy; Anxiety; Anticonvulsants
PubMed: 36946485
DOI: 10.2174/1570159X21666230322143401 -
The Patient Jul 2024The history of clinical trials is fraught with unethical practices. Since 1945, robust frameworks have evolved to standardise the collection and reporting of safety... (Review)
Review
BACKGROUND AND OBJECTIVE
The history of clinical trials is fraught with unethical practices. Since 1945, robust frameworks have evolved to standardise the collection and reporting of safety data, most notably, the Common Terminology Criteria for Adverse Events (CTCAE) from the National Cancer Institute; used by investigators to report side effects experienced by participants. As medicine moves into the patient-centred model, interest has been growing to collect data on adverse events directly from participants (patient-reported adverse events). The aim of this systematic scoping review was to investigate the inclusion of patient-reported adverse event data within safety/tolerability analyses and explore the collection and reporting of patient-reported adverse event data.
METHODS AND RESULTS
A database search was undertaken and the Covidence platform was used to manage the review; results were analysed descriptively. Sixty-eight studies were included in the analysis. An increase in the number of studies that incorporate patient-reported adverse event data was seen by year. Seventy instruments were used for the collection of patient-reported adverse event data with recall period, mode, frequency and site of administration varying across studies; the duration of data collection ranged from 28 days to 6 years. Frequently, information on these details was omitted from publications. The number of instruments used by studies to collect patient-reported adverse event data ranged from one to seven instruments.
CONCLUSIONS
Despite growing calls for the inclusion of patient-reported adverse events, this has not yet translated into published reports. The collection and reporting of these data were variable and conducted using instruments that were not designed for purpose. To address these inconsistencies, standardisation of data collection and reporting using a purpose-built validated instrument is required.
Topics: Humans; Neoplasms; Patient Reported Outcome Measures; Clinical Trials as Topic; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions
PubMed: 38589749
DOI: 10.1007/s40271-024-00689-4