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The Cochrane Database of Systematic... Apr 2020Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on...
BACKGROUND
Disease-modifying pharmacological agents for transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) have become available in the last decade, but evidence on their efficacy and safety is limited. This review focuses on disease-modifying pharmacological treatment for TTR-related and other FAPs, encompassing amyloid kinetic stabilisers, amyloid matrix solvents, and amyloid precursor inhibitors.
OBJECTIVES
To assess and compare the efficacy, acceptability, and tolerability of disease-modifying pharmacological agents for familial amyloid polyneuropathies (FAPs).
SEARCH METHODS
On 18 November 2019, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We reviewed reference lists of articles and textbooks on peripheral neuropathies. We also contacted experts in the field. We searched clinical trials registries and manufacturers' websites.
SELECTION CRITERIA
We included randomised clinical trials (RCTs) or quasi-RCTs investigating any disease-modifying pharmacological agent in adults with FAPs. Disability due to FAP progression was the primary outcome. Secondary outcomes were severity of peripheral neuropathy, change in modified body mass index (mBMI), quality of life, severity of depression, mortality, and adverse events during the trial.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methodology.
MAIN RESULTS
The review included four RCTs involving 655 people with TTR-FAP. The manufacturers of the drugs under investigation funded three of the studies. The trials investigated different drugs versus placebo and we did not conduct a meta-analysis. One RCT compared tafamidis with placebo in early-stage TTR-FAP (128 randomised participants). The trial did not explore our predetermined disability outcome measures. After 18 months, tafamidis might reduce progression of peripheral neuropathy slightly more than placebo (Neuropathy Impairment Score (NIS) in the lower limbs; mean difference (MD) -3.21 points, 95% confidential interval (CI) -5.63 to -0.79; P = 0.009; low-certainty evidence). However, tafamidis might lead to little or no difference in the change of quality of life between groups (Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score; MD -4.50 points, 95% CI -11.27 to 2.27; P = 0.19; very low-certainty evidence). No clear between-group difference was found in the numbers of participants who died (risk ratio (RR) 0.65, 95% CI 0.11 to 3.74; P = 0.63; very low-certainty evidence), who dropped out due to adverse events (RR 1.29, 95% CI 0.30 to 5.54; P = 0.73; very low-certainty evidence), or who experienced at least one severe adverse event during the trial (RR 1.16, 95% CI 0.37 to 3.62; P = 0.79; very low-certainty evidence). One RCT compared diflunisal with placebo (130 randomised participants). At month 24, diflunisal might reduce progression of disability (Kumamoto Score; MD -4.90 points, 95% CI -7.89 to -1.91; P = 0.002; low-certainty evidence) and peripheral neuropathy (NIS plus 7 nerve tests; MD -18.10 points, 95% CI -26.03 to -10.17; P < 0.001; low-certainty evidence) more than placebo. After 24 months, changes from baseline in the quality of life measured by the 36-Item Short-Form Health Survey score showed no clear difference between groups for the physical component (MD 6.10 points, 95% CI 2.56 to 9.64; P = 0.001; very low-certainty evidence) and the mental component (MD 4.40 points, 95% CI -0.19 to 8.99; P = 0.063; very low-certainty evidence). There was no clear between-group difference in the number of people who died (RR 0.46, 95% CI 0.15 to 1.41; P = 0.17; very low-certainty evidence), in the number of dropouts due to adverse events (RR 2.06, 95% CI 0.39 to 10.87; P = 0.39; very low-certainty evidence), and in the number of people who experienced at least one severe adverse event (RR 0.77, 95% CI 0.18 to 3.32; P = 0.73; very low-certainty evidence) during the trial. One RCT compared patisiran with placebo (225 randomised participants). After 18 months, patisiran reduced both progression of disability (Rasch-built Overall Disability Scale; least-squares MD 8.90 points, 95% CI 7.00 to 10.80; P < 0.001; moderate-certainty evidence) and peripheral neuropathy (modified NIS plus 7 nerve tests - Alnylam version; least-squares MD -33.99 points, 95% CI -39.86 to -28.13; P < 0.001; moderate-certainty evidence) more than placebo. At month 18, the change in quality of life between groups favoured patisiran (Norfolk QOL-DN total score; least-squares MD -21.10 points, 95% CI -27.20 to -15.00; P < 0.001; low-certainty evidence). There was little or no between-group difference in the number of participants who died (RR 0.61, 95% CI 0.21 to 1.74; P = 0.35; low-certainty evidence), dropped out due to adverse events (RR 0.33, 95% CI 0.13 to 0.82; P = 0.017; low-certainty evidence), or experienced at least one severe adverse event (RR 0.91, 95% CI 0.64 to 1.28; P = 0.58; low-certainty evidence) during the trial. One RCT compared inotersen with placebo (172 randomised participants). The trial did not explore our predetermined disability outcome measures. From baseline to week 66, inotersen reduced progression of peripheral neuropathy more than placebo (modified NIS plus 7 nerve tests - Ionis version; MD -19.73 points, 95% CI -26.50 to -12.96; P < 0.001; moderate-certainty evidence). At week 65, the change in quality of life between groups favoured inotersen (Norfolk QOL-DN total score; MD -10.85 points, 95% CI -17.25 to -4.45; P < 0.001; low-certainty evidence). Inotersen may slightly increase mortality (RR 5.94, 95% CI 0.33 to 105.60; P = 0.22; low-certainty evidence) and occurrence of severe adverse events (RR 1.48, 95% CI 0.85 to 2.57; P = 0.16; low-certainty evidence) compared to placebo. More dropouts due to adverse events were observed in the inotersen than in the placebo group (RR 8.57, 95% CI 1.16 to 63.07; P = 0.035; low-certainty evidence). There were no studies addressing apolipoprotein AI-FAP, gelsolin-FAP, and beta-2-microglobulin-FAP.
AUTHORS' CONCLUSIONS
Evidence on the pharmacological treatment of FAPs from RCTs is limited to TTR-FAP. No studies directly compare disease-modifying pharmacological treatments for TTR-FAP. Results from placebo-controlled trials indicate that tafamidis, diflunisal, patisiran, and inotersen may be beneficial in TTR-FAP, but further investigations are needed. Since direct comparative studies for TTR-FAP will be hampered by sample size and costs required to demonstrate superiority of one drug over another, long-term non-randomised open-label studies monitoring their efficacy and safety are needed.
Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Diflunisal; Disease Progression; Humans; Oligonucleotides; Patient Dropouts; Quality of Life; RNA, Small Interfering; Randomized Controlled Trials as Topic
PubMed: 32311072
DOI: 10.1002/14651858.CD012395.pub2 -
Scientific Reports Sep 2017Temporal lobe epilepsy (TLE) is a common chronic neurological disease in humans. A number of studies have demonstrated differential expression of miRNAs in the... (Meta-Analysis)
Meta-Analysis
Temporal lobe epilepsy (TLE) is a common chronic neurological disease in humans. A number of studies have demonstrated differential expression of miRNAs in the hippocampus of humans with TLE and in animal models of experimental epilepsy. However, the dissimilarities in experimental design have led to largely discordant results across these studies. Thus, a comprehensive comparison is required in order to better characterize miRNA profiles obtained in various post-status epilepticus (SE) models. We therefore created a database and performed a meta-analysis of differentially expressed miRNAs across 3 post-SE models of epileptogenesis (electrical stimulation, pilocarpine and kainic acid) and human TLE with hippocampal sclerosis (TLE-HS). The database includes data from 11 animal post-SE studies and 3 human TLE-HS studies. A total of 378 differentially expressed miRNAs were collected (274 up-regulated and 198 down-regulated) and analyzed with respect to the post-SE model, time point and animal species. We applied the novel robust rank aggregation method to identify consistently differentially expressed miRNAs across the profiles. It highlighted common and unique miRNAs at different stages of epileptogenesis. The pathway analysis revealed involvement of these miRNAs in key pathogenic pathways underlying epileptogenesis, including inflammation, gliosis and deregulation of the extracellular matrix.
Topics: Animals; Biomarkers; Computational Biology; Disease Models, Animal; Epilepsy, Temporal Lobe; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Genetic Association Studies; Genetic Predisposition to Disease; Humans; MicroRNAs; Oligonucleotide Array Sequence Analysis; Signal Transduction; Species Specificity
PubMed: 28912503
DOI: 10.1038/s41598-017-11510-8 -
The Cochrane Database of Systematic... Jul 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Opioids are used worldwide for the treatment of pain. They bind to opioid receptors in the central nervous system (mu, kappa, delta, and sigma) and can be agonists, antagonists, mixed agonist-antagonists, or partial agonists. Opioids are generally available in healthcare settings across most high-income countries, but access may be restricted in low- and middle-income countries. For example, opioids currently available in the UK include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are used in varying doses (generally based on body weight for paediatric patients) by means of parenteral, transmucosal, transdermal, or oral administration (immediate release or modified release). To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is a lower dose gradually titrated to effect in the child.
OBJECTIVES
To assess the analgesic efficacy and adverse events of opioids used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing opioids with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.
MAIN RESULTS
No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome.
AUTHORS' CONCLUSIONS
There was no evidence from randomised controlled trials to support or refute the use of opioids to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of opioids to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that some opioids, such as morphine and codeine, can be effective in certain chronic pain conditions.This means that no conclusions could be made about efficacy or harm in the use of opioids to treat chronic non-cancer pain in children and adolescents.
Topics: Adolescent; Analgesics, Opioid; Child; Child, Preschool; Chronic Pain; Humans; Infant; Infant, Newborn
PubMed: 28745394
DOI: 10.1002/14651858.CD012538.pub2 -
International Journal of Antimicrobial... Mar 2024Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of... (Review)
Review
Peptide nucleic acids (PNAs) are synthetic molecules that are like DNA/RNA, but with different building blocks. PNAs target and bind to mRNAs and disrupt the function of a targeted gene, hence they have been studied as potential antibacterials. The aim of this systematic review was to provide an in-depth analysis of the current status of PNAs as antibacterial agents, define the characteristics of the effective PNA constructs, and address the gap in advancing PNAs to become clinically competent agents. Following the PRISMA model, four electronic databases were searched: Web of Science, PubMed, SciFinder and Scopus. A total of 627 articles published between 1994 and 2023 were found. After screening and a rigorous selection process using explicit inclusion and exclusion criteria, 65 scientific articles were selected, containing 656 minimum inhibitory concentration (MIC) data. The antibacterial activity of PNAs was assessed against 20 bacterial species. The most studied Gram-negative and Gram-positive bacteria were Escherichia coli (n=266) and Staphylococcus aureus (n=53), respectively. In addition, the effect of PNA design, including construct length, binding location, and carrier agents, on antibacterial activity was shown. Finally, antibacterial test models to assess the inhibitory effects of PNAs were examined, emphasising gaps and prospects. This systematic review provides a comprehensive assessment of the potential of PNAs as antibacterial agents and offers valuable insights for researchers and clinicians seeking novel therapeutic strategies in the context of increasing rates of antibiotic-resistant bacteria.
Topics: Anti-Bacterial Agents; Bacteria; Peptide Nucleic Acids; Staphylococcus aureus
PubMed: 38185398
DOI: 10.1016/j.ijantimicag.2024.107083 -
The Cochrane Database of Systematic... Nov 2014Proliferative diabetic retinopathy (PDR) is a complication of diabetic retinopathy that can cause blindness. Although panretinal photocoagulation (PRP) is the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Proliferative diabetic retinopathy (PDR) is a complication of diabetic retinopathy that can cause blindness. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. An alternative treatment such as anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR.
OBJECTIVES
To assess the effectiveness and safety of anti-VEGFs for PDR.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing anti-VEGFs to another active treatment, sham treatment or no treatment for people with PDR. We also included studies that assessed the combination of anti-VEGFs with other treatments.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI).
MAIN RESULTS
We included 18 RCTs with 1005 participants (1131 eyes) of whom 57% were men. The median number of participants per RCT was 40 (range 15 to 261). The studies took place in Asia (three studies), Europe (two studies), the Middle East (seven studies), North America (three studies) and South America (three studies). Eight RCTs recruited people eligible for PRP, nine RCTs enrolled people with diabetes requiring vitrectomy and one RCT recruited people undergoing cataract surgery. The median follow-up was six months (range one to 12 months). Seven studies were at high risk of bias and the remainder were unclear risk of bias in one or more domains.Very low quality evidence from one study of 61 people showed that people treated with bevacizumab and PRP were less likely to lose 3 or more lines of visual acuity at 12 months compared with people treated with PRP alone (RR 0.19, 95% CI 0.05 to 0.81). People treated with anti-VEGF had an increased chance of gaining 3 or more lines of visual acuity but the effect was imprecise and compatible with no effect or being less likely to gain vision (RR 6.78, 95% CI 0.37 to 125.95). No other study reported these two outcomes. On average, people treated with anti-VEGF (bevacizumab, pegaptanib or ranibizumab) had better visual acuity at 12 months compared with people not receiving anti-VEGF (MD -0.07 logMAR, 95% CI -0.12 to -0.02; 5 RCTs, 373 participants, low quality evidence). There was some evidence to suggest a regression of PDR with smaller leakage on fluorescein angiography but it was difficult to estimate a pooled result from the two trials reporting this outcome. People receiving anti-VEGF were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.32, 95% CI 0.16 to 0.65; 3 RCTs, 342 participants, low quality evidence). No study reported on fluorescein leakage or quality of life.All of the nine trials of anti-VEGF before or during vitrectomy investigated bevacizumab; most studies investigated bevacizumab before vitrectomy, one study investigated bevacizumab during surgery.People treated with bevacizumab and vitrectomy were less likely to lose 3 or more lines of visual acuity at 12 months compared with people given vitrectomy alone but the effect was imprecise and compatible with no effect or being more likely to lose vision (RR 0.49, 95% CI 0.08 to 3.14; 3 RCTs, 94 participants, low quality evidence). People treated with bevacizumab were more likely to gain 3 or more lines of visual acuity (RR 1.62, 95% CI 1.20 to 2.17; 3 RCTs, 94 participants, low quality evidence). On average, people treated with bevacizumab had better visual acuity at 12 months compared with people not receiving bevacizumab but there was uncertainty in the estimate (the CIs included 0; i.e. were compatible with no effect, and there was considerable inconsistency between studies; MD -0.24 logMAR, 95% CI -0.50 to 0.01; 6 RCTs, 335 participants, I(2) = 67%; low quality evidence). People receiving bevacizumab were less likely to have vitreous or pre-retinal haemorrhage at 12 months (RR 0.30, 95% CI 0.18 to 0.52; 7 RCTs, 393 participants, low quality evidence). No study reported on quality of life.Reasons for downgrading the quality of the evidence included risk of bias in included studies, imprecision of the estimates, inconsistency of effect estimates and indirectness (few studies reported at 12 months).Adverse effects were rarely reported and there was no evidence for any increased risk with anti-VEGF but given the relatively few studies that reported these, and the low event rate, the power of the analysis to detect any differences was low.
AUTHORS' CONCLUSIONS
There was very low or low quality evidence from RCTs for the efficacy and safety of anti-VEGF agents when used to treat PDR over and above current standard treatments. However, the results suggest that anti-VEGFs can reduce the risk of intraocular bleeding in people with PDR. Further carefully designed clinical trials should be able to improve this evidence.
Topics: Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Bevacizumab; Diabetic Retinopathy; Female; Humans; Light Coagulation; Male; Randomized Controlled Trials as Topic; Ranibizumab; Vascular Endothelial Growth Factor A; Visual Acuity; Vitrectomy; Vitreoretinopathy, Proliferative
PubMed: 25418485
DOI: 10.1002/14651858.CD008721.pub2 -
Brain Imaging and Behavior Oct 2021While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in... (Review)
Review
While C9orf72-specific imaging signatures have been proposed by both ALS and FTD research groups and considerable presymptomatic alterations have also been confirmed in young mutation carriers, considerable inconsistencies exist in the literature. Accordingly, a systematic review of C9orf72-imaging studies has been performed to identify consensus findings, stereotyped shortcomings, and unique contributions to outline future directions. A formal literature review was conducted according to the STROBE guidelines. All identified papers were individually reviewed for sample size, choice of controls, study design, imaging modalities, statistical models, clinical profiling, and identified genotype-associated pathological patterns. A total of 74 imaging papers were systematically reviewed. ALS patients with GGGGCC repeat expansions exhibit relatively limited motor cortex involvement and widespread extra-motor pathology. C9orf72 positive FTD patients often show preferential posterior involvement. Reports of thalamic involvement are relatively consistent across the various phenotypes. Asymptomatic hexanucleotide repeat carriers often exhibit structural and functional changes decades prior to symptom onset. Common shortcomings included sample size limitations, lack of disease-controls, limited clinical profiling, lack of genetic testing in healthy controls, and absence of post mortem validation. There is a striking paucity of longitudinal studies and existing presymptomatic studies have not evaluated the predictive value of radiological changes with regard to age of onset and phenoconversion. With the advent of antisense oligonucleotide therapies, the meticulous characterisation of C9orf72-associated changes has gained practical relevance. Neuroimaging offers non-invasive biomarkers for future clinical trials, presymptomatic ascertainment, diagnostic and prognostic applications.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA Repeat Expansion; Frontotemporal Dementia; Humans; Magnetic Resonance Imaging; Proteins
PubMed: 33398779
DOI: 10.1007/s11682-020-00429-w -
Journal of Ocular Pharmacology and... Nov 2014The present study evaluates the safety of the biologics approved for the treatment of ocular diseases. (Review)
Review
PURPOSE
The present study evaluates the safety of the biologics approved for the treatment of ocular diseases.
METHODS
The European medicines agency Website was searched to identify biologics with approved ophthalmologic therapeutic indications. A systematic search was performed using MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and the International Clinical Trials Registry Platform up to December 2013. Pre-marketing, phase III randomized controlled trials (RCT), postmarketing clinical trials, observational longitudinal studies, and case reports involving adverse events (AE) were included. Methodological quality was assessed by Downs & Black checklist. All European spontaneous reports of AE included in the Eudravigilance up to December 2013 were also considered. AE were classified as ocular (related and non-related with the injection procedure) and non-ocular (related or non-related with vascular endothelial growth factor inhibition). Incidences of all reported AEs were estimated.
RESULTS
Pegaptanib, ranibizumab, and aflibercept were identified as ophthalmic biologics. Fourteen premarketing RCT, 7 postmarketing clinical trials, 31 observational studies, along with 31 case reports and 7,720 spontaneous reports were identified and included in this study. Both in pre- and postmarketing settings, ocular AEs were more frequent than non-ocular AEs. Premarketing safety data inform the most common AEs. Postmarketing studies suggest an increased number of events such as retinal pigmented epithelium tears (0.6%-24%), thromboembolic events (0.8%-5%), and mortality (2.8%-4%).
CONCLUSIONS
This study highlights the need to properly evaluate the risk for rare, serious, and long-term AEs, such as thromboembolic events, since they can lead to imbalances in the benefit-risk ratio of biologics in ophthalmology.
Topics: Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Biological Products; Eye Diseases; Humans; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retinal Pigment Epithelium; Thromboembolism; Vascular Endothelial Growth Factor A
PubMed: 25073069
DOI: 10.1089/jop.2013.0206 -
The Cochrane Database of Systematic... Jun 2017Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO.
OBJECTIVES
The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods.
SEARCH METHODS
We searched various electronic databases on 26 April 2017.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best-corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study.
MAIN RESULTS
Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate-certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 µm, 95% CI 2 µm to 76 µm; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 µm (95% CI -58 µm to -1 µm, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference.
AUTHORS' CONCLUSIONS
Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death.
Topics: Angiogenesis Inhibitors; Aptamers, Nucleotide; Bevacizumab; Diabetic Retinopathy; Humans; Laser Coagulation; Macular Edema; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Triamcinolone; Vascular Endothelial Growth Factor A; Visual Acuity
PubMed: 28639415
DOI: 10.1002/14651858.CD007419.pub5 -
Expert Opinion on Investigational Drugs Jul 2021Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains...
INTRODUCTION
Mood disorders are severe yet frequent psychiatric disorders worldwide, comprising major depressive disorder (MDD) and bipolar disorders (BD). Their treatment remains poorly effective. Recently, growing evidence for epigenetic mechanisms has emerged. Consequently, a great interest in a novel pharmacological class arose: RNA therapeutics.
AREAS COVERED
We conducted a systematic review of RNA therapeutics -antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), and micro-RNA (miRNA) therapeutics- for the treatment of mood disorders studied in pre-clinical animal models listed in PubMed, in clinical trials registered in ClinicalTrials.gov and available on the market by combining literature search and Food and Drug Administration and European Medicine Agency online databases. Eighteen pre-clinical studies investigated the antidepressant effects of RNA therapeutics. However, even though there is an increasing number of marketing authorizations and clinical trials for the past twenty years, no RNA therapeutic has reached the clinical development pipeline for the treatment of psychiatric disorders yet.
EXPERT OPINION
Several promising RNA therapeutics have been tested in pre-clinical studies for MDD, whereas no molecule has been developed for BD. There are several issues to address before reaching clinical development and new challenges include stratifying patient population and predicting therapeutic response.
Topics: Animals; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder, Major; Humans; Mood Disorders; RNA
PubMed: 33966550
DOI: 10.1080/13543784.2021.1928073 -
The Cochrane Database of Systematic... 2016Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis in fetal life. Recently, researchers have attempted to use anti-VEGF agents for the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis in fetal life. Recently, researchers have attempted to use anti-VEGF agents for the treatment of retinopathy of prematurity (ROP), a vasoproliferative disorder. There is currently uncertainty regarding the safety and efficacy of these agents in preterm infants with ROP.
OBJECTIVES
To evaluate the efficacy and safety of anti-VEGF drugs when used either as monotherapy, i.e. without concomitant cryotherapy or laser therapy or in combination with planned cryo/laser therapy in preterm infants with type 1 ROP (defined as zone I any stage with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 with plus disease).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (1966 to January 1, 2016), EMBASE (1980 to January 1, 2016), CINAHL (1982 to January 1, 2016), conference proceedings, and previous reviews.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials that evaluated the efficacy and safety of administration, or both, of anti-VEGF agents compared with conventional therapy in premature infants with ROP.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane and Cochrane Neonatal methods for data collection and analysis.
MAIN RESULTS
Three trials, in which 239 infants participated, fulfilled the inclusion criteria. Two trials compared intravitreal bevacizumab with conventional laser therapy (monotherapy) while the third compared intravitreal pegaptanib plus laser treatment with laser and cryotherapy (combination therapy) in infants with type 1 ROP.Of the two studies that evaluated intravitreal bevacizumab, one randomized infants while the other randomized eyes of the infants to the intervention and control groups. The former did not report any difference in the incidence of complete or partial retinal detachment between the groups (143 infants; RR 1.04, 95% CI 0.21 to 5.13; RD 0.00, 95% CI -0.06 to 0.07; very low quality evidence) but reported a significant reduction in the risk of refractive errors - very high myopia - at 30 months of age (211 eyes; RR 0.06, 95% CI 0.02 to 0.20; RD -0.40, 95% CI -0.50 to -0.30; low quality evidence) and recurrence of ROP by 54 weeks' postmenstrual age (143 infants; RR 0.22, 95% CI 0.08 to 0.62; RD -0.20, 95% CI -0.31 to -0.09; moderate quality evidence) in the bevacizumab group. The study found no difference in the risk of mortality before discharge from the hospital (150 infants; RR 1.50; 95% CI 0.26 to 8.75; RD 0.01; 95% CI -0.04 to 0.07; low quality evidence), mortality at 30 months of age (150 infants; RR 0.86, 95% CI 0.30 to 2.45; RD -0.01; 95% CI -0.10 to 0.08; low quality evidence), corneal opacity requiring corneal transplant (286 eyes; RR 0.34, 95% CI 0.01 to 8.26; RD -0.01; 95% CI -0.03 to 0.02; very low quality evidence), or lens opacity requiring cataract removal (286 eyes; RR 0.15, 95% CI 0.01 to 2.79; RD -0.02; 95% CI -0.05 to 0.01; very low quality evidence). The second trial that randomized eyes of the infants did not find any difference in the risk of complete retinal detachment between the eyes randomized to bevacizumab and those that were randomized to laser therapy (13 eyes; RR 0.33, 95% CI 0.01 to 7.50; RD -0.08, 95% CI -0.27 to 0.11).When used in combination with laser therapy, intravitreal pegaptanib was found to reduce the risk of retinal detachment when compared to laser/cryotherapy alone (152 eyes; RR 0.26, 95% CI 0.12 to 0.55; RD -0.29, 95% CI -0.42 to -0.16; low quality evidence). The incidence of recurrence of ROP by 55 weeks' postmenstrual age was also lower in the pegaptanib + laser therapy group (76 infants; RR 0.29, 95% CI 0.12 to 0.7; RD -0.35, 95% CI -0.55 to -0.16; low quality evidence). There was no difference in the risk of perioperative retinal haemorrhages between the two groups (152 eyes; RR 0.62, 95% CI 0.24 to 1.56; RD -0.05, 95% CI -0.16 to 0.05; very low quality evidence). The risk of delayed systemic adverse effects with either of the drugs is, however, not known.
IMPLICATIONS FOR PRACTICE
Intravitreal bevacizumab reduces the risk of refractive errors during childhood when used as monotherapy while intravitreal pegaptanib reduces the risk of retinal detachment when used in conjunction with laser therapy in infants with type 1 ROP. Quality of evidence was, however, low for both the outcomes because of the risk of detection and other biases. Effect on other critical outcomes and, more importantly, the long-term systemic adverse effects of the drugs are not known. The insufficient data precludes strong conclusions favouring routine use of intravitreal anti-VEGF agents in preterm infants with type 1 ROP.
IMPLICATIONS FOR RESEARCH
Further studies are needed to evaluate the effect of anti-VEGF agents on structural and functional outcomes in childhood and delayed systemic adverse effects such as myocardial dysfunction and adverse neurodevelopmental outcomes.
Topics: Angiogenesis Inhibitors; Aptamers, Nucleotide; Bevacizumab; Combined Modality Therapy; Cryotherapy; Humans; Infant, Newborn; Intravitreal Injections; Laser Therapy; Randomized Controlled Trials as Topic; Retinal Detachment; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A
PubMed: 26932750
DOI: 10.1002/14651858.CD009734.pub2