Midazolam versus morphine in acute cardiogenic pulmonary edema patients with and without atrial fibrillation: findings from the MIMO trial.

Effects of MIdazolam versus MOrphine in acute cardiogenic pulmonary edema and chronic obstructive pulmonary disease: An analysis of MIMO trial

A meta-analysis was performed to compare the risk of serious adverse events associated with the use of all formulations of isradipine, when used as monotherapy in hypertension, to active drug or placebo controls. Eligible studies totalled 65 published and unpublished randomised controlled trials involving 9903 subjects and 10,675 treatment exposures: 4492 to isradipine, 1473 to isradipine sustained release, 2768 to other active drugs, and 1942 to placebo. Mortality, cardiovascular outcomes, other serious incident illnesses, such as cancer, and withdrawals were sought. Seventy-five per cent of the isradipine exposures were to standard-release formulations and 25% were to sustained-release formulations. Overall, isradipine therapy shows no difference in risk of major adverse events or withdrawals compared to other active controls or placebo (odds ratios [OR] 0.9; 95% CI 0.7-1.46 and 0.5; 95% CI 0.2-1.3). These major adverse events included angina, fatal and non-fatal myocardial infarction, stroke and overall mortality. Isradipine sustained release could be compared only to placebo, based on available data, and shows a lower risk of withdrawals (OR 0.5; 95% CI 0.3-0.9), and a similar trend was observed for major adverse events, (OR 0.8; 95% CI 0.3-2.5). Published and unpublished randomised controlled trials were analysed in separate meta-analyses and later combined when this sensitivity analysis of risk showed no differences between the groups. In conclusion, we find no evidence for increased risk of serious adverse events in patients receiving isradipine as monotherapy for hypertension.

Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials

This update's findings for naldemedine and naloxone with oxycodone have been strengthened with two new trials, but conclusions have not changed. Moderate-certainty evidence for oral naldemedine on risk of spontaneous laxations and non-serious AEs suggests in people with cancer that naldemedine may improve bowel function over two weeks and increase the risk of AEs. There was low-certainty evidence on serious AEs. Moderate-certainty evidence for methylnaltrexone on spontaneous laxations over two weeks suggests subcutaneous methylnaltrexone may improve bowel function in people receiving palliative care, but certainty of evidence for AEs was low. More trials are needed, more evaluation of AEs, outcomes patients rate as important, and in children.

BackgroundCOVID-19 is a rapidly spreading disease that has caused extensive burden toindividuals, families, countries, and the world. Effective treatments ofCOVID-19 are urgently needed. This is the second edition of a livingsystematic review of randomized clinical trials assessing the effects of alltreatment interventions for participants in all age groups withCOVID-19.Methods and findingsWe planned to conduct aggregate data meta-analyses, trial sequentialanalyses, network meta-analysis, and individual patient data meta-analyses.Our systematic review was based on PRISMA and Cochrane guidelines, and oureight-step procedure for better validation of clinical significance ofmeta-analysis results. We performed both fixed-effect and random-effectsmeta-analyses. Primary outcomes were all-cause mortality and serious adverseevents. Secondary outcomes were admission to intensive care, mechanicalventilation, renal replacement therapy, quality of life, and non-seriousadverse events. According to the number of outcome comparisons, we adjustedour threshold for significance to p = 0.033. We used GRADEto assess the certainty of evidence. We searched relevant databases andwebsites for published and unpublished trials until November 2, 2020. Tworeviewers independently extracted data and assessed trial methodology. Weincluded 82 randomized clinical trials enrolling a total of 40,249participants. 81 out of 82 trials were at overall high risk of bias.Meta-analyses showed no evidence of a difference between corticosteroidsversus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidenceinterval [CI] 0.79 to 1.00; p = 0.05; I2 =23.1%; eight trials; very low certainty), on serious adverse events (RR0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%;eight trials; very low certainty), and on mechanical ventilation (RR 0.86;95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; twotrials; very low certainty). The fixed-effect meta-analyses showedindications of beneficial effects. Trial sequential analyses showed that therequired information size for all three analyses was not reached.Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31;I2 = 0%; four trials; moderate certainty) and trialsequential analysis (boundary for futility crossed) showed that we couldreject that remdesivir versus control reduced the risk of death by 20%.Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05;I2 = 38.9%; four trials; very low certainty) and trialsequential analysis (required information size not reached) showed noevidence of difference between remdesivir versus control on serious adverseevents. Fixed-effect meta-analysis showed indications of a beneficial effectof remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19to 0.87; p = 0.02; I2 = 0%; two trials; very lowcertainty) showed evidence of a beneficial effect of intravenousimmunoglobulin versus control on all-cause mortality, but trial sequentialanalysis (required information size not reached) showed that the result wasseverely underpowered to confirm or reject realistic intervention effects.Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12;I2 = 77.4%; five trials; very low certainty) and trialsequential analysis (required information size not reached) showed noevidence of a difference between tocilizumab versus control on seriousadverse events. Fixed-effect meta-analysis showed indications of abeneficial effect of tocilizumab on serious adverse events. Meta-analysis(RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 =0%; three trials; very low certainty) showed evidence of a beneficial effectof tocilizumab versus control on mechanical ventilation, but trialsequential analysis (required information size not reached) showed that theresult was severely underpowered to confirm of reject realistic interventioneffects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p< 0.00; I2 = 0%; two trials; very low certainty) showedevidence of a beneficial effect of bromhexine versus standard care onnon-serious adverse events, but trial sequential analysis (requiredinformation size not reached) showed that the result was severelyunderpowered to confirm or reject realistic intervention effects.Meta-analyses and trial sequential analyses (boundary for futility crossed)showed that we could reject that hydroxychloroquine versus control reducedthe risk of death and serious adverse events by 20%. Meta-analyses and trialsequential analyses (boundary for futility crossed) showed that we couldreject that lopinavir-ritonavir versus control reduced the risk of death,serious adverse events, and mechanical ventilation by 20%. All remainingoutcome comparisons showed that we did not have enough information toconfirm or reject realistic intervention effects. Nine single trials showedstatistically significant results on our outcomes, but were underpowered toconfirm or reject realistic intervention effects. Due to lack of data, itwas not relevant to perform network meta-analysis or possible to performindividual patient data meta-analyses.ConclusionsNo evidence-based treatment for COVID-19 currently exists. Very low certaintyevidence indicates that corticosteroids might reduce the risk of death,serious adverse events, and mechanical ventilation; that remdesivir mightreduce the risk of serious adverse events; that intravenous immunoglobinmight reduce the risk of death and serious adverse events; that tocilizumabmight reduce the risk of serious adverse events and mechanical ventilation;and that bromhexine might reduce the risk of non-serious adverse events.More trials with low risks of bias and random errors are urgently needed.This review will continuously inform best practice in treatment and clinicalresearch of COVID-19.Systematic review registrationPROSPERO CRD42020178787.

Physical activity and serious adverse events in patients with atrial fibrillation and/or atrial flutter treated with catheter ablation

BackgroundPostoperative pain is a common condition following orthopaedic surgeries and causes prolonged hospitalisation, delayed rehabilitation and hamper the quality of life. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are effective analgesics and anti‐inflammatory mediators in the treatment of postoperative pain. The association of NSAIDs with serious adverse events may however keep some clinicians and clinical decision makers from using NSAIDs perioperatively. The evidence regarding the risks of serious adverse events following perioperative use of NSAIDs in orthopaedic surgery is sparse and needs to be assessed in a systematic review. This is a protocol for a systematic review that aims to identify the risks of serious adverse events from perioperative use of NSAIDs in orthopaedic patients.MethodsOur methodology is based on the Preferred Reporting Items for Systematic Review and Meta‐Analysis Protocols and the eight‐step assessment procedure suggested by Jakobsen and colleagues. We wish to assess if NSAIDs versus placebo, usual care or no intervention, will influence the risks of serious adverse events in patients undergoing orthopaedic surgery. We will include all randomised trials assessing the use of NSAIDs perioperatively. To identify trials we will search the Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cochrane Central Register, Science Citation Index Expanded on Web of Science and BIOSIS. Two authors will screen the literature and extract data. We will use the ‘Risk of Bias 2 tool’ to assess trials. Extracted data will be analysed using RStudio and Trial Sequential Analysis. We will create a ‘Summary of Findings’ table in which we will present our primary and secondary outcomes. We will assess the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE).DiscussionThis systematic review can potentially aid clinicians and clinical decision makers in the use of NSAIDs for treatment of postoperative pain following orthopaedic surgeries.

The dictatorship of the Prague intellectuals

IntroductionIn 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials. MethodsSecondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults (NCT04368728 and NCT04470427), focusing analysis on Brighton Collaboration adverse events of special interest. ResultsPfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI −0.4 to 20.6 and −3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI –23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI −3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39). DiscussionThe excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.

ObjectiveTo evaluate the relative risk (RR) of serious and non-serious adverse events in patients treated with exercise therapy compared with those in a non-exercising control group.DesignSystematic review and meta-analysis.Data sourcesPrimary...

FMT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. The evidence was very uncertain about whether use of FMT in people with active UC impacted the risk of serious adverse events or improvement in quality of life. The evidence was also very uncertain about the use of FMT for maintenance of remission in people with UC, as well as induction and maintenance of remission in people with CD, and no conclusive statements could be made in this regard. Further studies are needed to address the beneficial effects and safety profile of FMT in adults and children with active UC and CD, as well as its potential to promote longer-term maintenance of remission in UC and CD.

Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for perioperative analgesic treatment. However, NSAID treatment may be associated with increased risk of adverse events. We investigated the risks of serious adverse events with perioperative NSAID treatment in patients undergoing orthopaedic surgery. We conducted a systematic review (PROSPERO: CRD42022342003) of randomised clinical trials assessing the harmful effects associated with the use of NSAIDs versus placebo, usual care, or no intervention in patients undergoing orthopaedic surgery. The primary outcome was the incidence of serious adverse events. We systematically searched for eligible trials up to October 13, 2025. We performed risk of bias assessments to account for systematic errors, Trial Sequential Analysis to account for the risks of random errors, performed meta-analyses using R, and used The Grading of Recommendations Assessment, Development and Evaluation framework to assess the certainty of the evidence. We included 38 trials enrolling 6593 patients for our primary outcome. Most trials were of high risk of bias. Meta-analysis showed no statistically significant difference between NSAID and placebo for risk of serious adverse events, RR 0.83; 95% CI, 0.61 to 1.14; p = 0.26; very low certainty of evidence. Post hoc beta-binomial regression sensitivity analyses, including trials with zero events, indicated no difference in risks of serious adverse events between NSAID and placebo (OR 0.89; 95% CI, 0.76 to 1.06; p = 0.19). Trial Sequential Analysis showed that insufficient information was obtained to confirm or reject a relative risk change of 25%. In adult patients undergoing orthopaedic surgery, we found no evidence of a difference between NSAID and placebo regarding risk of serious adverse events. However, the available data were insufficient to draw firm conclusions, and the certainty of evidence was generally very low. This systematic review with meta-analysis was aimed at assessing non-steroidal anti-inflammatory drug treatments for reported serious adverse effects in post-operative analgesia trials in orthopedic surgical cohorts. These drugs are routinely part of modern multimodal or pre-emptive analgesia treatment routines. The published evidence was generelly assessed to have a high risk of bias or low certainty for this specific question. No clear difference in reported event risk between this type of drug and placebo was found, though it is not clear that this is conclusive.

Antihypertensive prescribing and risk of adverse events in a female medicaid population

Epidemiological evidence has suggested a link between beta2-agonists and increased asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe. This is an updated systematic review. To assess the risk of mortality and non-fatal serious adverse events in trials which randomised patients with chronic asthma to regular salmeterol and inhaled corticosteroids in comparison to the same dose of inhaled corticosteroids. We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data. Food and Drug Administration (FDA) submissions in relation to salmeterol were also checked. The date of the most recent search is August 2012. We included parallel design controlled clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and inhaled corticosteroids (in separate or combined inhalers), and were of at least 12 weeks duration. We conducted the review according to standard procedures expected by the Cochrane Collaboration. We obtained unpublished data on mortality and serious adverse events from the sponsors, and from FDA submissions. We assessed the quality of evidence according to GRADE recommendations. We have included 35 studies (13,447 participants) in adults and adolescents, and 5 studies (1862 participants) in children in this review. We judged that the overall risk of bias was low, and we obtained data on serious adverse events from all studies. All except 542 adults (and none of the children) who were randomised to salmeterol were given fluticasone in the same (combination) inhaler.Seven deaths occurred in 6986 adults on regular salmeterol with inhaled corticosteroids (ICS), and seven deaths in 6461 adults on regular inhaled corticosteroids at the same dose. The difference was not statistically significant (Peto odds ratio (OR) 0.90; 95% confidence interval (CI) 0.31 to 2.60, moderate quality evidence). The risk of dying from any cause in adults on ICS was 10 per 10,000, and on salmeterol and ICS we would expect between 3 and 26 deaths per 10,000. No deaths were reported in 1862 children, and no deaths were reported to be asthma-related in adults or children.Non-fatal serious adverse events of any cause were reported in 167 adults on regular salmeterol with ICS, compared to 135 adults on regular ICS; again this was not a statistically significant increase (Peto OR 1.15; 95% CI 0.91 to 1.44, moderate quality evidence). The frequency of serious adverse events was 21 per 1000 in the adults treated with ICS and 24 per 1000 in those treated with salmeterol and ICS. The absolute difference in the risk of non-fatal serious adverse events was an increase of 3 per 1000, that was not statistically significant (risk difference (RD) 0.003; 95% CI -0.002 to 0.008).There were 6 of 930 children with serious adverse events on regular salmeterol with ICS, compared to 5 out of 932 on regular ICS: there was no significant difference between treatments (Peto OR 1.20; 95% CI 0.37 to 3.91, moderate quality evidence).Asthma-related serious adverse events were reported in 29 and 23 adults in each group respectively, a non-significant difference (Peto OR 1.12; 95% CI 0.65 to 1.94, moderate quality evidence), and only 1 asthma-related event was reported in children in each treatment group. We found no statistically significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS alone at the same dose. Although 13,447 adults and 1862 children have now been included in trials, the frequency of adverse events is too low and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events with salmeterol used in conjunction with ICS. However, the absolute difference between groups in the risk of serious adverse events was very small. We could not determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular ICS. We await the results of large ongoing surveillance studies mandated by the FDA to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.