Specification curve analysis to identify heterogeneity in risk factors for dementia: findings from the UK Biobank.

BACKGROUND: In 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer's disease strongly associated with dementia outcomes; however, it is unclear how robust these relationships are across dementia subtypes and analytic scenarios. Specification curve analysis (SCA) is a new tool to probe how plausible analytical scenarios influence outcomes. METHODS: We evaluated the heterogeneity of odds ratios for 12 risk factors reported from the Lancet 2020 report and two additional strong associated non-modifiable factors (APOE e4/e4 genotype and family history of Alzheimer's disease) with dementia outcomes across 450,707 UK Biobank participants using SCA with 5357 specifications across dementia subtypes (outcomes) and analytic models (e.g., standard demographic covariates such as age or sex and/or 14 correlated risk factors). RESULTS: SCA revealed variable dementia risks by subtype and age, with associations for TBI and APOE e4/e4 robust to model specification; in contrast, diabetes showed fluctuating links with dementia subtypes. We found that unattributed dementia participants had similar risk factor profiles to participants with defined subtypes. CONCLUSIONS: We observed heterogeneity in the risk of dementia, and estimates of risk were influenced by the inclusion of a combination of other modifiable risk factors; non-modifiable demographic factors had a minimal role in analytic heterogeneity. Future studies should report multiple plausible analytic scenarios to test the robustness of their association. Considering these combinations of risk factors could be advantageous for the clinical development and evaluation of novel screening models for different types of dementia.

Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.

BACKGROUND: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. PURPOSE: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. DATA SOURCES: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. STUDY SELECTION: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. DATA EXTRACTION: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. LIMITATIONS: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. CONCLUSION: Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. PRIMARY FUNDING SOURCE: None.

Anti-epithelial-derived cytokines for severe asthma: Systematic review and meta-analysis.

BACKGROUND: Therapies directed against epithelial-derived cytokines, often referred to as alarmins, have been studied in large randomized trials, and reports suggest possible benefit for non-type 2 as well as type 2 severe asthma. METHODS: We performed a systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process, and Web of Science databases from inception to March 2022. We performed a random-effects pairwise meta-analysis of randomized controlled trials addressing antialarmin therapy in severe asthma. Results use relative risk (RR) values and 95% confidence intervals (CIs). For continuous outcomes, we report mean difference (MD) values and 95% CIs. We define high eosinophils as ≥300 cells/µL and low eosinophils as <300 cells/µL. We used Cochrane-endorsed RoB 2.0 software to assess the risk of bias of trials, and we used the Grades of Recommendation Assessment, Development, and Evaluation (aka GRADE) framework to assess the certainty of the evidence. RESULTS: We identified 12 randomized trials including 2391 patients. Antialarmins probably reduce annualized exacerbation rates in patients with high eosinophils (RR 0.33 [95% CI 0.28 to 0.38]; moderate certainty). Antialarmins may reduce this rate in patients with low eosinophils (RR 0.59 [95% CI 0.38 to 0.90]; low certainty). Antialarmins improve FEV1 in patients with high eosinophils (MD 218.5 mL [95% CI 160.2 to 276.7]; high certainty). Antialarmin therapy probably does not improve FEV1 in patients with low eosinophils (MD 68.8 mL [95% CI 22.4 to 115.2]; moderate certainty). Antialarmins reduce blood eosinophils, total IgE, and fractional excretion of nitric oxide across studied subjects. CONCLUSION: Antialarmins are effective at improving lung function and probably reduce exacerbations in patients with severe asthma and blood eosinophils ≥300 cells/µL. The effect on patients with lower eosinophils is less certain.

Impact of Allocation Concealment and Blinding in Trials Addressing Treatments for COVID-19: A Methods Study.

We aimed to assess the impact of allocation concealment and blinding on the results of coronavirus disease 2019 (COVID-19) trials, using the World Health Organization COVID-19 database (to February 2022). We identified 488 randomized trials comparing drug therapeutics with placebo or standard care in patients with COVID-19. We performed random-effects meta-regressions comparing the results of trials with and without allocation concealment and blinding of health-care providers and patients. We found that, compared with trials with allocation concealment, trials without allocation concealment may estimate treatments to be more beneficial for mortality, mechanical ventilation, hospital admission, duration of hospitalization, and duration of mechanical ventilation, but results were imprecise. We did not find compelling evidence that, compared with trials with blinding, trials without blinding produce consistently different results for mortality, mechanical ventilation, and duration of hospitalization. We found that trials without blinding may estimate treatments to be more beneficial for hospitalizations and duration of mechanical ventilation. We did not find compelling evidence that COVID-19 trials in which health-care providers and patients are blinded produce different results from trials without blinding, but trials without allocation concealment estimate treatments to be more beneficial compared with trials with allocation concealment. Our study suggests that lack of blinding may not always bias results but that evidence users should remain skeptical of trials without allocation concealment.

Patient-Reported Outcome Measure Use in Guidelines Published by the American Academy of Ophthalmology: A Review.

TOPIC: We reviewed the use of patient-reported outcome measures (PROMs) in the treatment of ophthalmologic conditions as recommended by the Clinical Practice Guidelines (CPGs) published by the American Academy of Ophthalmology (AAO). CLINICAL RELEVANCE: Patient-reported outcome measures are standardized instruments that provide information regarding a patient's health status or health-related quality of life. Patient-reported outcome measures are increasingly used to inform study end points in ophthalmology studies. However, the extent to which PROMs are ultimately informing patient management recommendations in ophthalmology as part of CPGs remains an area of evidence gap. METHODS: We included all CPGs published by the AAO from inception to June 2022. We also included all primary studies and systematic reviews cited in the treatment sections of the CPGs evaluating treatment of an ophthalmic condition. The primary outcome was the frequency of PROMs discussed in CPGs and in cited studies evaluating treatment. Secondary outcomes included frequency of minimal important difference (MID) use to contextualize PROM results and percentage of strong and discretionary recommendations supported by PROMs. We published a study protocol a priori on PROSPERO (CRD42022307427). Reporting followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We assessed risk of bias using the Appraisal of Guidelines, Research and Evaluation II (AGREE II) instrument. RESULTS: We identified 24 eligible CPGs, providing 2458 cited studies (2191 primary, 267 secondary) evaluating treatment of eye conditions. Ten CPGs (41.7%) reported consideration of PROMs. Of these, 31 of 94 (33%) recommendations were informed by studies evaluating a PROM as an outcome. Across all studies cited in the development of CPGs, 221 (9.0%) used PROMs as a primary or secondary outcome, of which 4 PROM results (1.8%) were interpreted using an empirically determined MID. Overall, the risk of bias was low for all CPGs. CONCLUSIONS: Overall, outcomes of PROMs are seldom used in ophthalmology CPGs published by the AAO and in cited primary and secondary research on treatments. When PROMs were considered, their interpretation was seldom based on an MID. To improve patient care, guideline developers may consider incorporating PROMs and applicable MIDs to inform key outcomes when formulating treatment recommendations. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Corticosteroids in Community-Acquired Bacterial Pneumonia: a Systematic Review, Pairwise and Dose-Response Meta-Analysis.

INTRODUCTION: International guidelines provide heterogenous guidance on use of corticosteroids for community-acquired pneumonia (CAP). METHODS: We performed a systematic review of randomized controlled trials examining corticosteroids in hospitalized adult patients with suspected or probable CAP. We performed a pairwise and dose-response meta-analysis using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed the certainty of the evidence using GRADE methodology and the credibility of subgroups using the ICEMAN tool. RESULTS: We identified 18 eligible studies that included 4661 patients. Corticosteroids probably reduce mortality in more severe CAP (RR 0.62 [95% CI 0.45 to 0.85]; moderate certainty) with possibly no effect in less severe CAP (RR 1.08 [95% CI 0.83 to 1.42]; low certainty). We found a non-linear dose-response relationship between corticosteroids and mortality, suggesting an optimal dose of approximately 6 mg of dexamethasone (or equivalent) for a duration of therapy of 7 days (RR 0.44 [95% 0.30 to 0.66]). Corticosteroids probably reduce the risk of requiring invasive mechanical ventilation (RR 0.56 [95% CI 0.42 to 74] and probably reduce intensive care unit (ICU) admission (RR 0.65 [95% CI 0.43 to 0.97]) (both moderate certainty). Corticosteroids may reduce the duration of hospitalization and ICU stay (both low certainty). Corticosteroids may increase the risk of hyperglycemia (RR 1.76 [95% CI 1.46 to 2.14]) (low certainty). CONCLUSION: Moderate certainty evidence indicates that corticosteroids reduce mortality in patients with more severe CAP, the need for invasive mechanical ventilation, and ICU admission.

A comparison of the effectiveness of biologic therapies for asthma: A systematic review and network meta-analysis.

BACKGROUND: Trials have not directly compared biologics for the treatment of asthma. OBJECTIVE: To compare the relative efficacy of biologics in asthma. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to May 31, 2022 for randomized trials addressing biologic therapies for asthma. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. We present dichotomous outcomes as absolute risk differences per 1000 patients and relative risk with 95% confidence intervals (95% CI) and continuous outcomes as mean difference (MD) and 95% CI. RESULTS: We identified 64 trials, including 26,630 patients. For patients with eosinophilic asthma, tezepelumab (329 fewer exacerbations per 1000 [95% CI, 272.6-366.6 fewer]) and dupilumab (319.6 fewer exacerbations per 1000 [95% CI, 272.6-357.2 fewer]) reduce exacerbations compared with placebo (high certainty). Tezepelumab (MD, 0.24 L [95% CI, 0.16-0.32]) and dupilumab (0.25 L [95% CI, 0.21-0.29]) improve lung function compared with placebo (high certainty). Both tezepelumab (110.97 fewer hospital admissions per 1000 [95% CI, 94.53-120.56 fewer]) and dupilumab (97.27 fewer hospitalizations [4.11-124.67 fewer]) probably reduce hospital admissions compared with placebo (moderate certainty). For patients with low eosinophils, biologics probably do not improve asthma outcomes. For these patients, tezepelumab (MD, 0.1 L [95% CI, 0-0.19]) and dupilumab (MD, 0.1 L [95% CI, 0-0.20]) may improve lung function (low certainty). CONCLUSION: Tezepelumab and dupilumab are effective at reducing exacerbations. For patients with low eosinophils, however, clinicians should probably be more judicious in using biologics, including tezepelumab, because they probably do not confer substantial benefit.

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis.

Importance: Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. Objective: To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023. Study Selection: Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. Data Extraction and Synthesis: Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID). Main Outcomes and Measures: Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events. Results: Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]). Conclusions and Relevance: Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis.

OBJECTIVE: While there are several trials that support the efficacy of various drugs for migraine prophylaxis against placebo, there is limited evidence addressing the comparative safety and efficacy of these drugs. We conducted a systematic review and network meta-analysis to facilitate comparison between drugs for migraine prophylaxis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to August 13, 2022, for randomized trials of pharmacological treatments for migraine prophylaxis in adults. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist random-effects network meta-analysis and rated the certainty (quality) of evidence as either high, moderate, low, or very low using the GRADE approach. RESULTS: We identified 74 eligible trials, reporting on 32,990 patients. We found high certainty evidence that monoclonal antibodies acting on the calcitonin gene related peptide or its receptor (CGRP(r)mAbs), gepants, and topiramate increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo. We found moderate certainty evidence that beta-blockers, valproate, and amitriptyline increase the proportion of patients who experience a 50% or more reduction in monthly migraine days, and low certainty evidence that gabapentin may not be different from placebo. We found high certainty evidence that, compared to placebo, valproate and amitriptyline lead to substantial adverse events leading to discontinuation, moderate certainty evidence that topiramate, beta-blockers, and gabapentin increase adverse events leading to discontinuation, and moderate to high certainty evidence that (CGRP(r)mAbs) and gepants do not increase adverse events. CONCLUSIONS: (CGRP(r)mAbs) have the best safety and efficacy profile of all drugs for migraine prophylaxis, followed closely by gepants.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: flunarizine.

OBJECTIVE: Novel disease-specific and mechanism-based treatments sharing good evidence of efficacy for migraine have been recently marketed. However, reimbursement by insurers depends on treatment failure with classic anti-migraine drugs. In this systematic review and meta-analysis, we aimed to identify and rate the evidence for efficacy of flunarizine, a repurposed, first- or second-line treatment for migraine prophylaxis. METHODS: A systematic search in MEDLINE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Eligible trials for meta-analysis were randomized, placebo-controlled studies comparing flunarizine with placebo. Outcomes of interest according to the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) were the proportion of patients reaching a 50% or more reduction in monthly migraine days, the change in monthly migraine days (MMDs), and Adverse Events (AEs) leading to discontinuation. RESULTS: Five trials were eligible for narrative description and three for data synthesis and analysis. No studies reported the predefined outcomes, but one study assessed the 50% reduction in monthly migraine attacks with flunarizine as compared to placebo showing a benefit from flunarizine with a low or probably low risk of bias. We found that flunarizine may increase the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.02; 95% CI -0.03 to 0.06). CONCLUSIONS: Published flunarizine trials predate the recommended endpoints for evaluating migraine prophylaxis drugs, hence the lack of an adequate assessment for these endpoints. Further, modern-day, large-scale studies would be valuable in re-evaluating the efficacy of flunarizine for the treatment of migraines, offering additional insights into its potential benefits.

European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: amitriptyline.

OBJECTIVE: The aim of this paper is to critically re-appraise the published trials assessing amitriptyline for migraine prophylaxis. METHODS: We report our methods and results following the Preferred Reporting Items for Systematic Reviews (PRISMA), by searching MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov for randomized trials of pharmacologic treatments for migraine prophylaxis. We included randomized trials that compared amitriptyline with placebo for migraine prophylaxis in adults. Our outcomes of interest were informed by the Outcome Set for preventive intervention trials in chronic and episodic migraine (COSMIG) and include the proportion of patients who experience a 50% or more reduction in migraine days per month, migraine days per month, and adverse events leading to discontinuation. We assessed risk of bias by using a modified Cochrane RoB 2.0 tool and the certainty of evidence by using the GRADE approach. RESULTS: Our search yielded 10.826 unique records, of which three trials (n = 622) were eligible for data synthesis and analysis. We found moderate certainty evidence that amitriptyline increases the proportion of patients who experience a 50% or more reduction in monthly migraine days, compared to placebo (relative risk: 1.60 (95% CI 1.17 to 2.19); absolute risk difference: 165 more per 1,000 (95% CI 47 more to 327 more). We found moderate certainty evidence that amitriptyline increases the proportion of patients who discontinue due to adverse events compared to placebo (risk difference: 0.05 (95% CI 0.01 to 0.10); absolute risk difference: 50 more per 1,000 (95% CI 10 more to 100 more). CONCLUSIONS: Our meta-analysis showed that amitriptyline may have a prophylactic role in migraine patients, however these results are far from robust. This warrants further large-scale research to evaluate the role of amitriptyline in migraine prevention.

European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention - part 3: topiramate.

OBJECTIVE: Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate. METHODS: A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework. RESULTS: Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29-2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41-0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)]. CONCLUSIONS: There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care.

Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework. RESULTS: We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (-88.35 to 411.12)), pirfenidone (2.47% (-0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty). CONCLUSION AND RELEVANCE: Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs). DATA SOURCES: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception. STUDY SELECTION AND DATA EXTRACTION: Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data. DATA SYNTHESIS: We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty). CONCLUSIONS: Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.

Sildenafil for idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis have a poor overall prognosis and there are few evidence-based drug therapies that reduce mortality. OBJECTIVE: We aimed to perform a systematic review and meta-analysis to assess whether sildenafil reduces mortality, disease progression and adverse side effects. METHODS: We reviewed randomized controlled studies (RCTs) from MEDLINE, Cochrane registry of clinical trials, and EMBASE. Our outcomes of interest included mortality, change in FVC, acute exacerbations and hospitalizations and adverse drug effects leading to discontinuation. We used an inverse variance fixed effects meta-analysis method to calculate pooled relative risk (RR) and mean difference (MD). RESULTS: A total of 4 studies were included in the systematic review. Sildenafil probably reduces mortality when compared to placebo or to standard care, [RR 0.73 (95% CI 0.51 to 1.04); moderate certainty]. Pooled estimates showed sildenafil may not alter the rate of change of FVC [MD 0.61% (95% CI -0.29 to 1.52)], or DLCO [MD 0.97% (95% CI 0.04 to 1.90)] (both low certainty). Pooled estimated showed sildenafil may not reduce the number of hospitalizations or acute exacerbations, [RR 1.10 (95% CI 0.61 to 1.98); low certainty]. There is probably no difference in drug discontinuation due to adverse effects when comparing sildenafil to the control group, [RR 0.79 (95% CI 0.56, 1.10); moderate certainty]. CONCLUSION: Sildenafil probably reduces all-cause mortality in IPF patients. More studies need to be done to confirm the magnitude and reliability of the point estimate.

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis.

BACKGROUND: Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear. METHODS: We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir-ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir-ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty). INTERPRETATION: Molnupiravir and nirmatrelvir-ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir-ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Inhaled corticosteroids, COPD, and the incidence of lung cancer: a systematic review and dose response meta-analysis.

BACKGROUND: There has been debate on whether inhaled corticosteroids (ICS) reduce the incidence of lung cancer amongst patients with Chronic Obstructive Lung Disease (COPD). We aimed to perform a systematic review and dose-response meta-analysis on available observational data. METHODS: We performed both a dose response and high versus low random effects meta-analysis on observational studies measuring whether lung cancer incidence was lower in patients using ICS with COPD. We report relative risk (RR) with 95% confidence intervals (CI), as well as risk difference. We use the GRADE framework to report our results. RESULTS: Our dose-response suggested a reduction in the incidence of lung cancer for every 500 ug/day of fluticasone equivalent ICS (RR 0.82 [95% 0.68-0.95]). Using a baseline risk of 7.2%, we calculated risk difference of 14 fewer cases per 1000 ([95% CI 24.7-3.8 fewer]). Similarly, our results suggested that for every 1000 ug/day of fluticasone equivalent ICS, there was a larger reduction in incidence of lung cancer (RR 0.68 [0.44-0.93]), with a risk difference of 24.7 fewer cases per 1000 ([95% CI 43.2-5.4 fewer]). The certainty of the evidence was low to very low, due to risk of bias and inconsistency. CONCLUSION: There may be a reduction in the incidence for lung cancer in COPD patients who use ICS. However, the quality of the evidence is low to very low, therefore, we are limited in making strong claims about the true effect of ICS on lung cancer incidence.

Drug-drug interactions with warfarin: A systematic review and meta-analysis.

AIMS: The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes. METHODS: MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens. CONCLUSIONS: This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.

Evidence Collection and Evaluation for the Development of Dietary Guidelines and Public Policy on Nutrition.

Dietary guidelines and recommendations, usually developed by government bodies or large authoritative organizations, have major downstream effects on public policy. A growing body of evidence supports the notion that there are serious deficiencies in the methods used to develop dietary guidelines. Such deficiencies include the failure to access or conduct comprehensive systematic reviews, a lack of systematic or rigorous evaluation of the quality of the evidence, a failure to acknowledge the limitations of the evidence base underlying recommendations, and insufficiently stringent management of conflicts of interest. These issues may be addressed by adhering to international standards for guideline development, including adopting systematic review methodology and using rigorous systems to evaluate the certainty of the evidence and to move from evidence to recommendations, of which the GRADE approach (Grading of Recommendations Assessment,Development and Evaluation) is the most rigorous and fully developed. Improving the methods by which dietary guidelines are produced has considerable potential to substantially improve public policy decision-making.

Red and Processed Meat Consumption and Risk for All-Cause Mortality and Cardiometabolic Outcomes: A Systematic Review and Meta-analysis of Cohort Studies.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Background: Dietary guidelines generally recommend limiting intake of red and processed meat. However, the quality of evidence implicating red and processed meat in adverse health outcomes remains unclear. Purpose: To evaluate the association between red and processed meat consumption and all-cause mortality, cardiometabolic outcomes, quality of life, and satisfaction with diet among adults. Data Sources: EMBASE (Elsevier), Cochrane Central Register of Controlled Trials (Wiley), Web of Science (Clarivate Analytics), CINAHL (EBSCO), and ProQuest from inception until July 2018 and MEDLINE from inception until April 2019, without language restrictions, as well as bibliographies of relevant articles. Study Selection: Cohort studies with at least 1000 participants that reported an association between unprocessed red or processed meat intake and outcomes of interest. Data Extraction: Teams of 2 reviewers independently extracted data and assessed risk of bias. One investigator assessed certainty of evidence, and the senior investigator confirmed the assessments. Data Synthesis: Of 61 articles reporting on 55 cohorts with more than 4 million participants, none addressed quality of life or satisfaction with diet. Low-certainty evidence was found that a reduction in unprocessed red meat intake of 3 servings per week is associated with a very small reduction in risk for cardiovascular mortality, stroke, myocardial infarction (MI), and type 2 diabetes. Likewise, low-certainty evidence was found that a reduction in processed meat intake of 3 servings per week is associated with a very small decrease in risk for all-cause mortality, cardiovascular mortality, stroke, MI, and type 2 diabetes. Limitation: Inadequate adjustment for known confounders, residual confounding due to observational design, and recall bias associated with dietary measurement. Conclusion: The magnitude of association between red and processed meat consumption and all-cause mortality and adverse cardiometabolic outcomes is very small, and the evidence is of low certainty. Primary Funding Source: None. (PROSPERO: CRD42017074074).