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JAMA Oncology Dec 2018Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data.
OBJECTIVE
To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects.
DESIGN, SETTING, AND PARTICIPANTS
We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally.
EXPOSURES
Anti-CTLA-4 (ipilimumab or tremelimumab), anti-PD-1 (nivolumab, pembrolizumab), or anti-PD-L1 (atezolizumab, avelumab, durvalumab).
MAIN OUTCOMES AND MEASURES
Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects.
RESULTS
Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti-CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti-PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4).
CONCLUSIONS AND RELEVANCE
In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.
Topics: Antineoplastic Agents, Immunological; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Genes, cdc; Humans; Immunologic Factors; Immunotherapy; Incidence; Neoplasms; Pharmacovigilance; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 30242316
DOI: 10.1001/jamaoncol.2018.3923 -
Orphanet Journal of Rare Diseases Jun 2020Duchenne Muscular Dystrophy (DMD) is a rare disorder caused by mutations in the dystrophin gene. A recent systematic review and meta-analysis of global DMD epidemiology... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Duchenne Muscular Dystrophy (DMD) is a rare disorder caused by mutations in the dystrophin gene. A recent systematic review and meta-analysis of global DMD epidemiology is not available. This study aimed to estimate the global overall and birth prevalence of DMD through an updated systematic review of the literature.
METHODS
MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of DMD from inception until 1st October 2019. Studies were included if they were original observational research articles written in English, reporting DMD prevalence and/or incidence along with the number of individuals of the underlying population. The quality of the studies was assessed using a STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist adapted for observational studies on rare diseases. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using random-effects logistic models for overall and birth prevalence and within two different underlying populations (i.e. all individuals and in males only), separately. Heterogeneity was assessed using Cochran's Q-test along with its derived measure of inconsistency I.
RESULTS
A total of 44 studies reporting the global epidemiology of DMD were included in the systematic review and only 40 were included in the meta-analysis. The pooled global DMD prevalence was 7.1 cases (95% CI: 5.0-10.1) per 100,000 males and 2.8 cases (95% CI: 1.6-4.6) per 100,000 in the general population, while the pooled global DMD birth prevalence was 19.8 (95% CI:16.6-23.6) per 100,000 live male births. A very high between-study heterogeneity was found for each epidemiological outcome and for all underlying populations (I > 90%). The test for funnel plot asymmetry suggested the absence of publication bias. Of the 44 studies included in this systematic review, 36 (81.8%) were assessed as being of medium and 8 (18.2%) of low quality, while no study was assessed as being of high quality.
CONCLUSIONS
Generating epidemiological evidence on DMD is fundamental to support public health decision-making. The high heterogeneity and the lack of high quality studies highlights the need to conduct better quality studies on rare diseases.
Topics: Humans; Incidence; Male; Muscular Dystrophy, Duchenne; Prevalence; Rare Diseases
PubMed: 32503598
DOI: 10.1186/s13023-020-01430-8 -
EBioMedicine Mar 2023To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing...
BACKGROUND
To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy.
METHODS
The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence.
FINDINGS
PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects.
INTERPRETATION
This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.
FUNDING
None.
Topics: Male; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Autoimmune Diseases; Biomarkers; Psoriasis; Polymorphism, Single Nucleotide; TYK2 Kinase
PubMed: 36842216
DOI: 10.1016/j.ebiom.2023.104488 -
European Respiratory Review : An... Dec 2022Respiratory syncytial virus (RSV) significantly impacts the health of older and high-risk adults (those with comorbidities). We aimed to synthesise the evidence on RSV... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Respiratory syncytial virus (RSV) significantly impacts the health of older and high-risk adults (those with comorbidities). We aimed to synthesise the evidence on RSV disease burden and RSV-related healthcare utilisation in both populations.
METHODS
We searched Embase and MEDLINE for papers published between 2000 and 2019 reporting the burden and clinical presentation of symptomatic RSV infection and the associated healthcare utilisation in developed countries in adults aged ≥60 years or at high risk. We calculated pooled estimates using random-effects inverse variance-weighted meta-analysis.
RESULTS
103 out of 3429 articles met the inclusion criteria. Among older adults, RSV caused 4.66% (95% CI 3.34-6.48%) of symptomatic respiratory infections in annual studies and 7.80% (95% CI 5.77-10.45%) in seasonal studies; RSV-related case fatality proportion (CFP) was 8.18% (95% CI 5.54-11.94%). Among high-risk adults, RSV caused 7.03% (95% CI 5.18-9.48%) of symptomatic respiratory infections in annual studies, and 7.69% (95% CI 6.23-9.46%) in seasonal studies; CFP was 9.88% (95% CI 6.66-14.43%). Data paucity impaired the calculation of estimates on population incidence, clinical presentation, severe outcomes and healthcare-related utilisation.
CONCLUSIONS
Older and high-risk adults frequently experience symptomatic RSV infection, with appreciable mortality; however, detailed data are lacking. Increased surveillance and research are needed to quantify population-based disease burden and facilitate RSV treatments and vaccine development.
Topics: Humans; Aged; Respiratory Syncytial Virus Infections; Developed Countries; Hospitalization; Respiratory Syncytial Virus, Human; Respiratory Tract Infections
PubMed: 36384703
DOI: 10.1183/16000617.0105-2022 -
BMJ Open Jun 2016It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is... (Review)
Review
OBJECTIVE
It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue.
SETTING, PARTICIPANTS AND OUTCOME MEASURES
We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population.
RESULTS
We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found.
CONCLUSIONS
High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.
Topics: Aged; Cardiovascular Diseases; Cholesterol, LDL; Humans; Middle Aged; Mortality; Risk Factors
PubMed: 27292972
DOI: 10.1136/bmjopen-2015-010401 -
Pharmaceutical Medicine Oct 2022Artificial intelligence through machine learning uses algorithms and prior learnings to make predictions. Recently, there has been interest to include more artificial...
INTRODUCTION
Artificial intelligence through machine learning uses algorithms and prior learnings to make predictions. Recently, there has been interest to include more artificial intelligence in pharmacovigilance of products already in the market and pharmaceuticals in development.
OBJECTIVE
The aim of this study was to identify and describe the uses of artificial intelligence in pharmacovigilance through a systematic literature review.
METHODS
Embase and MEDLINE database searches were conducted for articles published from January 1, 2015 to July 9, 2021 using search terms such as 'pharmacovigilance,' 'patient safety,' 'artificial intelligence,' and 'machine learning' in the title or abstract. Scientific articles that contained information on the use of artificial intelligence in all modalities of patient safety or pharmacovigilance were reviewed and synthesized using a pre-specified data extraction template. Articles with incomplete information and letters to editor, notes, and commentaries were excluded.
RESULTS
Sixty-six articles were identified for evaluation. Most relevant articles on artificial intelligence focused on machine learning, and it was used in patient safety in the identification of adverse drug events (ADEs) and adverse drug reactions (ADRs) (57.6%), processing safety reports (21.2%), extraction of drug-drug interactions (7.6%), identification of populations at high risk for drug toxicity or guidance for personalized care (7.6%), prediction of side effects (3.0%), simulation of clinical trials (1.5%), and integration of prediction uncertainties into diagnostic classifiers to increase patient safety (1.5%). Artificial intelligence has been used to identify safety signals through automated processes and training with machine learning models; however, the findings may not be generalizable given that there were different types of data included in each source.
CONCLUSION
Artificial intelligence allows for the processing and analysis of large amounts of data and can be applied to various disease states. The automation and machine learning models can optimize pharmacovigilance processes and provide a more efficient way to analyze information relevant to safety, although more research is needed to identify if this optimization has an impact on the quality of safety analyses. It is expected that its use will increase in the near future, particularly with its role in the prediction of side effects and ADRs.
Topics: Artificial Intelligence; Drug-Related Side Effects and Adverse Reactions; Humans; Machine Learning; Pharmaceutical Preparations; Pharmacovigilance
PubMed: 35904529
DOI: 10.1007/s40290-022-00441-z -
European Neuropsychopharmacology : the... Dec 2017In the last ten years, gabapentin and pregabalin have been becoming dispensed broadly and sold on black markets, thereby, exposing millions to potential side-effects.... (Review)
Review
In the last ten years, gabapentin and pregabalin have been becoming dispensed broadly and sold on black markets, thereby, exposing millions to potential side-effects. Meanwhile, several pharmacovigilance-databases have warned for potential abuse liabilities and overdose fatalities in association with both gabapentinoids. To evaluate their addiction risk in more detail, we conducted a systematic review on PubMed/Scopus and included 106 studies. We did not find convincing evidence of a vigorous addictive power of gabapentinoids which is primarily suggested from their limited rewarding properties, marginal notes on relapses, and the very few cases with gabapentinoid-related behavioral dependence symptoms (ICD-10) in patients without a prior abuse history (N=4). In support, there was no publication about people who sought treatment for the use of gabapentinoids. Pregabalin appeared to be somewhat more addictive than gabapentin regarding the magnitude of behavioral dependence symptoms, transitions from prescription to self-administration, and the durability of the self-administrations. The principal population at risk for addiction of gabapentinoids consists of patients with other current or past substance use disorders (SUD), mostly opioid and multi-drug users, who preferred pregabalin. Pure overdoses of gabapentinoids appeared to be relative safe but can become lethal (pregabalin > gabapentin) in mixture with other psychoactive drugs, especially opioids again and sedatives. Based upon these results, we compared the addiction risks of gabapentin and pregabalin with those of traditional psychoactive substances and recommend that in patients with a history of SUD, gabapentinoids should be avoided or if indispensable, administered with caution by using a strict therapeutic and prescription monitoring.
Topics: Amines; Analgesics; Behavior, Addictive; Cyclohexanecarboxylic Acids; Databases, Bibliographic; Drug Overdose; Gabapentin; Humans; Pregabalin; Self Administration; Substance-Related Disorders; gamma-Aminobutyric Acid
PubMed: 28988943
DOI: 10.1016/j.euroneuro.2017.08.430 -
PloS One 2017Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for... (Meta-Analysis)
Meta-Analysis
The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials.
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents.
METHODS AND FINDINGS
We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library (up to April 7, 2016). Interventions of interest were pharmacological (stimulants, non-stimulants, antidepressants, antipsychotics, and other unlicensed drugs), psychological (behavioural, cognitive training and neurofeedback) and complementary and alternative medicine (dietary therapy, fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity). The primary outcomes were efficacy (treatment response) and acceptability (all-cause discontinuation). Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy (alone or in combination with stimulants), stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms (anorexia, weight loss and insomnia), but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution.
CONCLUSIONS
Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008.
Topics: Adolescent; Attention Deficit Disorder with Hyperactivity; Behavior Therapy; Central Nervous System Depressants; Central Nervous System Stimulants; Child; Complementary Therapies; Female; Humans; Male; Randomized Controlled Trials as Topic
PubMed: 28700715
DOI: 10.1371/journal.pone.0180355 -
European Journal of Clinical... Oct 2019Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic... (Meta-Analysis)
Meta-Analysis
PURPOSE
Tendinopathy is a known adverse reaction associated to fluoroquinolones, but a meta-analysis was not yet published. The aim of this study was to conduct a systematic review and a meta-analysis of the scientific evidence evaluating the risk of tendon injury associated with fluoroquinolones.
METHODS
A literature search was conducted to identify observational studies which reported results on the risk of Achilles tendon rupture (ATR), risk of Achilles tendinitis (AT), or risk of any tendon disorders (ATD). A meta-analysis was performed by pooling odds ratios (ORs) with their 95% confidence intervals (CIs).
RESULTS
Fifteen studies were included in the meta-analysis. Treatment with fluoroquinolones was associated with an increased risk of ATR (OR 2.52 (95% CI 1.81-3.52), p < 0.001, I = 76.7%), an increased risk of AT (OR 3.95 (95% CI 3.11-5.01), p < 0.001, I = 0%), and increased risk of ATD (OR 1.98 (95% CI 1.62-2.43), p < 0.001, I = 84.5%). The initial risk estimates remained statistically significant among patients aged ≥ 60 years old. Risk estimates did not significantly change after depending on the concomitant use of corticosteroids or studies methodological quality assessment. The analysis according to the type of fluoroquinolones was only possible for ATR, which were ofloxacin and norfloxacin were found to increase the risk of this outcome, but not ciprofloxacin and levofloxacin.
CONCLUSIONS
The results of this meta-analysis confirm the risk of tendon injuries associated with fluoroquinolones. Older age and concomitant use of corticosteroids seem to be additional risk factors for tendinopathy.
Topics: Fluoroquinolones; Humans; Observational Studies as Topic; Risk Factors; Tendon Injuries
PubMed: 31270563
DOI: 10.1007/s00228-019-02713-1 -
European Journal of Clinical... Sep 2023Proton pump inhibitors (PPIs) reduce acid secretion in the stomach and rank as one of the most widely used acid-suppressing medicines globally. While PPIs are safe in... (Review)
Review
PURPOSE
Proton pump inhibitors (PPIs) reduce acid secretion in the stomach and rank as one of the most widely used acid-suppressing medicines globally. While PPIs are safe in the short-term, emerging evidence shows risks associated with long-term use. Current evidence on global PPI use is scarce. This systematic review aims to evaluate global PPI use in the general population.
METHODS
Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts were systematically searched from inception to 31 March 2023 to identify observational studies on oral PPI use among individuals aged ≥ 18 years. PPI use was classified by demographics and medication factors (dose, duration, and PPI types). The absolute numbers of PPI users for each subcategory were summed and expressed as a percentage.
RESULTS
The search identified data from 28 million PPI users in 23 countries from 65 articles. This review indicated that nearly one-quarter of adults use a PPI. Of those using PPIs, 63% were less than 65 years. 56% of PPI users were female, and "White" ethnicities accounted for 75% of users. Nearly two-thirds of users were on high doses (≥ defined daily dose (DDD)), 25% of users continued PPIs for > 1 year, and 28% of these continued for > 3 years.
CONCLUSION
Given the widespread use PPIs and increasing concern regarding long-term use, this review provides a catalyst to support more rational use, particularly with unnecessary prolonged continuation. Clinicians should review PPI prescriptions regularly and deprescribe when there is no appropriate ongoing indication or evidence of benefit to reduce health harm and treatment cost.
Topics: Adult; Humans; Female; Male; Proton Pump Inhibitors; Upper Gastrointestinal Tract; Health Care Costs; Prescriptions
PubMed: 37420019
DOI: 10.1007/s00228-023-03534-z