scholarly journals Effects of adding ivabradine to usual care in patients with angina pectoris: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis

Open Heart ◽  
2020 ◽  
Vol 7 (2) ◽  
pp. e001288
Author(s):  
Mathias Maagaard ◽  
Emil Eik Nielsen ◽  
Naqash Javaid Sethi ◽  
Liang Ning ◽  
Si-hong Yang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Angina Pectoris ◽  
Adverse Events ◽  
Sequential Analysis ◽  
Randomised Clinical Trials ◽  
Trial Sequential Analysis ◽  
Serious Adverse Events ◽  
All Cause Mortality ◽  
Artery Disease

ObjectiveTo determine the impact of ivabradine on outcomes important to patients with angina pectoris caused by coronary artery disease.MethodsWe conducted a systematic review. We included randomised clinical trials comparing ivabradine versus placebo or no intervention for patients with angina pectoris due to coronary artery disease published prior to June 2020. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, Cochrane methodology, Trial Sequential Analysis, Grading of Recommendations Assessment, Development, and Evaluation, and our eight-step procedure. Primary outcomes were all-cause mortality, serious adverse events and quality of life.ResultsWe included 47 randomised clinical trials enrolling 35 797 participants. All trials and outcomes were at high risk of bias. Ivabradine compared with control did not have effects when assessing all-cause mortality (risk ratio [RR] 1.04; 95% CI 0.96 to 1.13), quality of life (standardised mean differences −0.05; 95% CI −0.11 to 0.01), cardiovascular mortality (RR 1.07; 95% CI 0.97 to 1.18) and myocardial infarction (RR 1.03; 95% CI 0.91 to 1.16). Ivabradine seemed to increase the risk of serious adverse events after removal of outliers (RR 1.07; 95% CI 1.03 to 1.11) as well as the following adverse events classified as serious: bradycardia, prolonged QT interval, photopsia, atrial fibrillation and hypertension. Ivabradine also increased the risk of non-serious adverse events (RR 1.13; 95% CI 1.11 to 1.16). Ivabradine might have a statistically significant effect when assessing angina frequency (mean difference (MD) 2.06; 95% CI 0.82 to 3.30) and stability (MD 1.48; 95% CI 0.07 to 2.89), but the effect sizes seemed minimal and possibly without any relevance to patients, and we identified several methodological limitations, questioning the validity of these results.ConclusionOur findings do not support that ivabradine offers significant benefits on patient important outcomes, but rather seems to increase the risk of serious adverse events such as atrial fibrillation and non-serious adverse events. Based on current evidence, guidelines need reassessment and the use of ivabradine for angina pectoris should be reconsidered.PROSPERO registration numberCRD42018112082.

scholarly journals Ivabradine added to usual care in patients with heart failure: a systematic review with meta-analysis and trial sequential analysis

2021 ◽  
pp. bmjebm-2021-111724
Author(s):  
Mathias Maagaard ◽  
Emil Eik Nielsen ◽  
Naqash Javaid Sethi ◽  
Ning Liang ◽  
Si-Hong Yang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adverse Events ◽  
Usual Care ◽  
Sequential Analysis ◽  
Meta Analysis ◽  
Risk Of Bias ◽  
Trial Sequential Analysis ◽  
Serious Adverse Events ◽  
All Cause Mortality

ObjectivesTo assess the beneficial and harmful effects of adding ivabradine to usual care in participants with heart failure.DesignA systematic review with meta-analysis and trial sequential analysis.Eligibility criteriaRandomised clinical trials comparing ivabradine and usual care with usual care (with or without) placebo in participants with heart failure.Information sourcesMedline, Embase, CENTRAL, LILACS, CNKI, VIP and other databases and trial registries up until 31 May 2021.Data extractionPrimary outcomes were all-cause mortality, serious adverse events and quality of life. Secondary outcomes were cardiovascular mortality, myocardial infarction and non-serious adverse events. We performed meta-analysis of all outcomes. We used trial sequential analysis to control risks of random errors, the Cochrane risk of bias tool to assess the risks of systematic errors and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence.ResultsWe included 109 randomised clinical trials with 26 567 participants. Two trials were at low risk of bias, although both trials were sponsored by the company that developed ivabradine. All other trials were at high risk of bias. Meta-analyses and trial sequential analyses showed that we could reject that ivabradine versus control reduced all-cause mortality (risk ratio (RR)=0.94; 95% CI 0.88 to 1.01; p=0.09; high certainty of evidence). Meta-analysis and trial sequential analysis showed that ivabradine seemed to reduce the risk of serious adverse events (RR=0.90; 95% CI 0.87 to 0.94; p<0.00001; number needed to treat (NNT)=26.2; low certainty of evidence). This was primarily due to a decrease in the risk of ‘cardiac failure’ (RR=0.83; 95% CI 0.71 to 0.97; p=0.02; NNT=43.9), ‘hospitalisations’ (RR=0.89; 95% CI 0.85 to 0.94; p<0.0001; NNT=36.4) and ‘ventricular tachycardia’ (RR=0.59; 95% CI 0.43 to 0.82; p=0.001; NNT=212.8). However, the trials did not describe how these outcomes were defined and assessed during follow-up. Meta-analyses showed that ivabradine increased the risk of atrial fibrillation (RR=1.19; 95% CI 1.04 to 1.35; p=0.008; number needed to harm (NNH)=116.3) and bradycardia (RR=3.95; 95% CI 1.88 to 8.29; p=0.0003; NNH=303). Ivabradine seemed to increase quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean difference (MD)=2.92; 95% CI 1.34 to 4.50; p=0.0003; low certainty of evidence), but the effect size was small and possibly without relevance to patients, and on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ) (MD=−5.28; 95% CI −6.60 to −3.96; p<0.00001; very low certainty of evidence), but the effects were uncertain. Meta-analysis showed no evidence of a difference between ivabradine and control when assessing cardiovascular mortality and myocardial infarction. Ivabradine seemed to increase the risk of non-serious adverse events.Conclusion and relevanceHigh certainty evidence shows that ivabradine does not seem to affect the risks of all-cause mortality and cardiovascular mortality. The effects on quality of life were small and possibly without relevance to patients on the KCCQ and were very uncertain for the MLWHFQ. The effects on serious adverse events, myocardial infarction and hospitalisation are uncertain. Ivabradine seems to increase the risk of atrial fibrillation, bradycardia and non-serious adverse events.PROSPERO registration number: CRD42018112082.

scholarly journals Ketamine for critically ill patients with severe acute brain injury: Protocol for a systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259899
Author(s):  
Frederik Andreas Madsen ◽  
Trine Hjorslev Andreasen ◽  
Jane Lindschou ◽  
Christian Gluud ◽  
Kirsten Møller
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Brain Injury ◽  
Functional Outcome ◽  
Sequential Analysis ◽  
Acute Brain Injury ◽  
Randomised Clinical Trials ◽  
Trial Sequential Analysis ◽  
Secondary Brain Injury ◽  
Serious Adverse Events

Introduction Intensive care for patients with severe acute brain injury aims both to treat the immediate consequences of the injury and to prevent and treat secondary brain injury to ensure a good functional outcome. Sedation may be used to facilitate mechanical ventilation, for treating agitation, and for controlling intracranial pressure. Ketamine is an N-methyl-D-aspartate receptor antagonist with sedative, analgesic, and potentially neuroprotective properties. We describe a protocol for a systematic review of randomised clinical trials assessing the beneficial and harmful effects of ketamine for patients with severe acute brain injury. Methods and analysis We will systematically search international databases for randomised clinical trials, including CENTRAL, MEDLINE, Embase, and trial registries. Two authors will independently review and select trials for inclusion, and extract data. We will compare ketamine by any regimen versus placebo, no intervention, or other sedatives or analgesics for patients with severe acute brain injury. The primary outcomes will be functional outcome at maximal follow up, quality of life, and serious adverse events. We will also assess secondary and exploratory outcomes. The extracted data will be analysed using Review Manager and Trials Sequential Analysis. Evidence certainty will be graded using GRADE. Ethics and dissemination The results of the systematic review will be disseminated through peer-reviewed publication. With the review, we hope to inform future randomised clinical trials and improve clinical practice. PROSPERO no CRD42021210447.

scholarly journals Exercise for patients with major depression: a systematic review with meta-analysis and trial sequential analysis

BMJ Open ◽  
2017 ◽  
Vol 7 (9) ◽  
pp. e014820 ◽  
Author(s):  
Jesper Krogh ◽  
Carsten Hjorthøj ◽  
Helene Speyer ◽  
Christian Gluud ◽  
Merete Nordentoft
Keyword(s):  
Quality Of Life ◽  
Systematic Review ◽  
Adverse Events ◽  
Sequential Analysis ◽  
Trial Sequential Analysis ◽  
Depression Severity ◽  
Serious Adverse Events ◽  
Secondary Outcomes

ObjectivesTo assess the benefits and harms of exercise in patients with depression.DesignSystematic reviewData sourcesBibliographical databases were searched until 20 June 2017.Eligibility criteria and outcomesEligible trials were randomised clinical trials assessing the effect of exercise in participants diagnosed with depression. Primary outcomes were depression severity, lack of remission and serious adverse events (eg, suicide) assessed at the end of the intervention. Secondary outcomes were quality of life and adverse events such as injuries, as well as assessment of depression severity and lack of remission during follow-up after the intervention.ResultsThirty-five trials enrolling 2498 participants were included. The effect of exercise versus control on depression severity was −0.66 standardised mean difference (SMD) (95% CI −0.86 to −0.46; p<0.001; grading of recommendations assessment, development and evaluation (GRADE): very low quality). Restricting this analysis to the four trials that seemed less affected of bias, the effect vanished into −0.11 SMD (−0.41 to 0.18; p=0.45; GRADE: low quality). Exercise decreased the relative risk of no remission to 0.78 (0.68 to 0.90; p<0.001; GRADE: very low quality). Restricting this analysis to the two trials that seemed less affected of bias, the effect vanished into 0.95 (0.74 to 1.23; p=0.78). Trial sequential analysis excluded random error when all trials were analysed, but not if focusing on trials less affected of bias. Subgroup analyses found that trial size and intervention duration were inversely associated with effect size for both depression severity and lack of remission. There was no significant effect of exercise on secondary outcomes.ConclusionsTrials with less risk of bias suggested no antidepressant effects of exercise and there were no significant effects of exercise on quality of life, depression severity or lack of remission during follow-up. Data for serious adverse events and adverse events were scarce not allowing conclusions for these outcomes.Systematic review registrationThe protocol was published in the journalSystematic Reviews: 2015; 4:40.

scholarly journals Psychotherapy versus treatment as usual and other control interventions in children and adolescents with overweight and obesity: a protocol for systematic review with meta-analysis and Trial Sequential Analysis

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e036058
Author(s):  
Rajeeb Rashid ◽  
Laura Condon ◽  
Christian Gluud ◽  
Janus C Jakobsen ◽  
Jane Lindschou ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Children And Adolescents ◽  
Sequential Analysis ◽  
Meta Analysis ◽  
Overweight And Obesity ◽  
Trial Sequential Analysis ◽  
Serious Adverse Events ◽  
Treatment As Usual

IntroductionThe prevalence of children with overweight and obesity is increasing worldwide. Multicomponent interventions incorporating diet, physical activity and behavioural change have shown limited improvement to body mass index (BMI). However, the impact of psychotherapy is poorly explored. This systematic review aims to assess the effects of psychotherapeutic approaches for children with all degrees of overweight.Methods and analysisWe will include randomised clinical trials involving children and adolescents between 0 and 18 years with overweight and obesity, irrespective of publication type, year, status or language up to April 2020. Psychotherapy will be compared with no intervention; wait list control; treatment as usual; sham psychotherapy or pharmaceutical placebo. The following databases will be searched: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, MEDLINE, Embase, PsycINFO, PubMed, Web of Science, CINAHL and LILACS. Primary outcomes will be BMI z-score, quality of life measured by a validated scale and proportion of patients with serious adverse events. Secondary outcomes will be body weight, self-esteem, anxiety, depression and proportion of patients with non-serious adverse events. Exploratory outcomes will be body fat, muscle mass and serious adverse events. Study inclusion, data extraction and bias risk assessments will be conducted independently by at least two authors. We will assess risk of bias according to Cochrane guidelines and the Cochrane Effective Practice and Organisation of Care guidance. We will use meta-analysis and control risks of random errors with Trial Sequential Analysis. The quality of the evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation Tool. The systematic review will be reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines.Ethics and disseminationAs individual patient data will not be included, we do not require ethics approval. This review will be published in a peer review journal.PROSPERO registration numberCRD42018086458.

scholarly journals Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Shaolei Ma ◽  
Changsheng Xu ◽  
Shijiang Liu ◽  
Xiaodi Sun ◽  
Renqi Li ◽  
...  
Keyword(s):  
Adverse Events ◽  
Randomized Controlled Trials ◽  
Disease Progression ◽  
Sequential Analysis ◽  
Trial Sequential Analysis ◽  
Controlled Trials ◽  
Cochrane Central Register ◽  
Serious Adverse Events ◽  
Randomized Controlled ◽  
All Cause Mortality

AbstractThe benefits and harms of corticosteroids for patients with severe coronavirus disease 2019 (COVID-19) remain unclear. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from December 31, 2019 to October 1, 2020 to identify randomized controlled trials (RCTs) that evaluated corticosteroids in severe COVID-19 patients. The primary outcome was all-cause mortality at the longest follow-up. Secondary outcomes included a composite disease progression (progression to intubation, ventilation, extracorporeal membrane oxygenation, ICU transfer, or death among those not ventilated at enrollment) and incidence of serious adverse events. A random-effects model was applied to calculate risk ratio (RR) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation approach to evaluate the certainty of the evidence. Seven RCTs involving 6250 patients were included, of which the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial comprised nearly 78% of all included subjects. Results showed that corticosteroids were associated with a decreased all-cause mortality (27.3 vs. 31.1%; RR: 0.85; 95% CI: 0.73–0.99; P = 0.04; low-certainty evidence). Trial sequential analysis suggested that more trials were still required to confirm the results. However, such survival benefit was absent if RECOVERY trial was excluded (RR: 0.83; 95% CI: 0.65–1.06; P = 0.13). Furthermore, corticosteroids decreased the occurrence of composite disease progression (30.6 vs. 33.3%; RR: 0.77; 95% CI: 0.64–0.92; P = 0.005), but not increased the incidence of serious adverse events (3.5 vs. 3.4%; RR: 1.16; 95% CI: 0.39–3.43; P = 0.79).

scholarly journals Prompt closure versus gradual weaning of extraventricular drainage for hydrocephalus in adult patients with aneurysmal subarachnoid haemorrhage: a systematic review protocol with meta-analysis and trial sequential analysis

BMJ Open ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. e029719 ◽  
Author(s):  
Tenna Capion ◽  
Alexander Lilja-Cyron ◽  
Marianne Juhler ◽  
Tiit Illimar Mathiesen ◽  
Jørn Wetterslev
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Subarachnoid Haemorrhage ◽  
Sequential Analysis ◽  
Adult Patients ◽  
Randomised Clinical Trials ◽  
Trial Sequential Analysis ◽  
Aneurysmal Subarachnoid Haemorrhage ◽  
Increased Risk

IntroductionIn Neuro Intensive Care Units (NICU) and neurosurgical units, patients with an external ventricular drain (EVD) due to hydrocephalus following aneurysmal subarachnoid haemorrhage (SAH) are commonly seen. Cessation of the EVD involves the dilemma of either closing the EVD directly, or gradually weaning it before removal. Development of increased intracranial pressure (ICP) and acute hydrocephalus with subsequent need of a permanent shunt has been associated with prompt closure of theEVD, whereas increased risk of infection with possible spreading to the brain and subsequent patient fatality is suspected in connection to a longer treatment as seen in gradual weaning. Sparse data exist on the recommendation of cessation strategy and patients are currently being treated on the basis of personal experience and expert opinion. The objective of this systematic review is to assess the available evidence from clinical trials on the effects of prompt closure versus gradual weaning of EVD treatment for hydrocephalus in adult patients with SAH.Methods and analysisWe will search for randomised clinical trials in major international databases. Two authors will independently screen and select references for inclusion, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager and trial sequential analysis. To assess the quality of the evidence, we will create a ‘Summary of Findings’ table containing our primary and secondary outcomes using the GRADE assessment.Ethics and disseminationResults will be published widely according to the interest of the society. No possible impact, harm or ethical concerns are expected doing this protocol.Trial registration numberPROSPERO CRD42018108801

scholarly journals The effects of adding glucocorticosteroids to standard care for children with sepsis. A systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis

2021 ◽  
Author(s):  
Steven Kwasi Korang ◽  
Sanam Safi ◽  
Christian Gluud ◽  
Janus C Jakobsen
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Standard Care ◽  
Sequential Analysis ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Trial Sequential Analysis ◽  
Serious Adverse Events ◽  
Meta Analyses

Abstract Background: Glucocorticosteroids are widely used to treat severe sepsis in pediatric intensive care units. However, the evidence on the clinical effects is unclear.Objective: To assess the benefits and harms of glucocorticosteroids for children with sepsis. Data Sources: We conducted a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis (TSA) (PROSPERO CRD42017054341). We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, and more. Study Selection: Randomized clinical trials assessing the effects of adding glucocorticosteroids to standard care for children with sepsis. Data Extraction: Two independent reviewers screened studies and extracted data. Evidence was assessed by GRADE according to our published protocol.Data Synthesis: We included 24 trials randomizing 3073 participants. Meta-analyses showed no evidence of an effect of adding glucocorticosteroids for children with sepsis with a mixed focus for any of our outcomes. Meta-analyses suggested evidence of a beneficial effect of dexamethasone for children with meningitis when assessing serious adverse events (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.53 to 0.86; P = 0.001, very low certainty of evidence) and ototoxicity (RR 0.63, 95% CI 0.45 to 0.88; P = 0.007, low certainty of evidence). TSAs showed that we did not have sufficient data to confirm or reject these results. We found insufficient evidence to confirm or reject an effect on mortality or our other outcomes. No trials reported quality of life or organ failure. Most trials were at high risks of bias. We found high clinical heterogeneity between participants. None of our TSAs showed benefits, harms or futility. Conclusions: Generally, we found no evidence of an effect of glucocorticosteroids for children with sepsis without meningitis. Dexamethasone for sepsis in children due to meningitis may decrease serious adverse events and ototoxicity.

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