Beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis
The Cochrane database of systematic reviews. 2021;1:Cd011973
BACKGROUND Portal hypertension commonly accompanies advanced liver disease and often gives rise to life-threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Variceal haemorrhage commonly occurs in children with chronic liver disease or portal vein thrombosis. Therefore, prevention is important. Band ligation, beta-blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding in children. However, primary prophylaxis is not the current standard of care in paediatric patients because it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children and adolescents. OBJECTIVES To determine the benefits and harms of beta-blockers compared with placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase, LILACS, and Science Citation Index Expanded (April 2020). We screened the reference lists of the retrieved publications and manually searched the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstract books from 2008 to December 2019. We searched clinicaltrials.gov, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) for ongoing clinical trials. We imposed no language or document type restrictions on our search. SELECTION CRITERIA We planned to include randomised clinical trials, irrespective of blinding, language, or publication status to assess benefits and harms. We included observational studies, retrieved with the searches for randomised clinical trials, for a narrative report of harm. DATA COLLECTION AND ANALYSIS We planned to summarise data from randomised clinical trials by standard Cochrane methodologies. We planned to asses risk of bias and use GRADE to assess the certainty of evidence. Our primary outcomes were all-cause mortality, serious adverse events and liver-related morbidity, and health-related quality of life. Our secondary outcomes were oesophageal variceal bleeding and adverse events not considered serious. We planned to use intention-to-treat principle. We planned to analyse data with RevMan Analysis. MAIN RESULTS We found no randomised clinical trials that assessed beta-blockers compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We found four observational studies that reported on harms. As a systematic search for observational studies was not planned, we only listed the reported harms in a table. AUTHORS' CONCLUSIONS Randomised clinical trials assessing the benefits or harms of beta-blockers versus placebo or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are lacking. Therefore, trials with adequate power and proper design, assessing the benefits and harms of beta-blockers versus placebo on patient-relevant clinical outcomes, such as mortality, quality of life, failure to control variceal bleeding, and adverse events are needed. Unless such trials are conducted and the results become published, we cannot make any conclusions regarding the benefits or harms of the two interventions.
Mortality after Bleeding versus Myocardial Infarction in Coronary Artery Disease: A Systematic Review and Meta-Analysis
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2021
BACKGROUND Bleeding is the principal safety concern of antithrombotic therapy and occurs frequently among patients with coronary artery disease (CAD). AIMS We aim to evaluate the prognostic impact of bleeding on mortality compared with that of myocardial infarction (MI) in patients with CAD. METHODS We searched Medline and Embase for studies that included patients with CAD and that reported both, the association between the occurrence of bleeding and mortality, and between the occurrence of MI and mortality within the same population. Adjusted hazard ratios (HRs) for mortality associated with bleeding and MI were extracted and ratio of hazard ratios (rHRs) were pooled by using inverse variance weighted random effects meta-analyses. Early events included periprocedural or within 30-day events after revascularization or acute coronary syndrome (ACS). Late events included spontaneous or beyond 30-day events after revascularization or ACS. RESULTS 141,059 patients were included across 16 studies and 128,660 (91%) underwent percutaneous coronary intervention. Major bleeding, increased the risk of mortality to the same extent of MI (rHRbleedingvs.MI 1.10, 95%CI, 0.71-1.71, P=0.668). Early bleeding was associated with a higher risk of mortality than early MI (rHRbleedingvs.MI 1.46, 95%CI, 1.13-1.89, P=0.004), although this finding was not present when only randomized trials were included. Late bleeding was prognostically comparable to late MI (rHRbleedingvs.MI 1.14, 95%CI, 0.87-1.49, P=0.358). CONCLUSIONS Compared with MI, major and late bleeding is associated with a similar increase in mortality, whereas early bleeding might have a stronger association with mortality.
Evaluation of pentoxifylline and ferrous sulfate for treatment of lower limb venous ulcers
Jornal vascular brasileiro. 2021;20:e2020167
BACKGROUND Venous ulcers (VU) are the most advanced stage of chronic venous disease (CVD) of the lower limbs. They are frequently associated with episodes of hemorrhage that can provoke chronic anemia (CA), delaying healing. There are no studies in the literature analyzing the prevalence of CA among patients with VU of the lower limbs and few studies have analyzed use of pentoxifylline to treat VU of the lower limbs. OBJECTIVES To evaluate the prevalence of CA in patients with lower limb VU and responses to treatment with ferrous sulfate (SF) compared with a combination of SF plus pentoxifylline as adjuvant treatment for VU of the lower limbs. METHODS A total of 67 patients with lower limb VU were recruited from a Lymphedema and Angiodysplasia Clinic at the Hospital das Clínicas, Recife, PE, Brazil. After initial clinical and laboratory assessments, patients diagnosed with CA were randomized into one of two groups: a control group, given SF (900 mg/day oral route), or a study group, treated with SF (900 mg/day oral route) and pentoxifylline (1,200 mg/day). All were reassessed after 90 days. RESULTS Twenty-seven patients (40%) had CA. After treatment, increases were observed in hemoglobin and hematocrit levels, iron kinetics had improved, and both depth and area of VU had reduced in both groups, without statistically significant differences. CONCLUSIONS A high prevalence of anemia was detected in the study population. The combination of SF and pentoxifylline was not more effective than SF alone for adjuvant treatment of VU of the lower limbs.
Ferric carboxymaltose for the treatment of iron deficiency in heart failure: a multinational cost-effectiveness analysis utilising AFFIRM-AHF
European journal of heart failure. 2021
AIMS: Iron deficiency is common in patients with heart failure (HF). In AFFIRM-AHF, ferric carboxymaltose (FCM) reduced the risk of hospitalisations for HF (HHF) and improved quality of life vs. placebo in iron-deficient patients with a recent episode of acute HF. The objective of this study was to estimate the cost-effectiveness of FCM compared with placebo in iron-deficient patients with left ventricular ejection fraction <50%, stabilised after an episode of acute HF, using data from the AFFIRM-AHF trial from Italian, UK, US and Swiss payer perspectives. METHODS AND RESULTS A lifetime Markov model was built to characterise outcomes in patients according to the AFFIRM-AHF trial. Health states were defined using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Subsequent HHF were incorporated using a negative binomial regression model with cardiovascular and all-cause mortality incorporated via parametric survival analysis. Direct healthcare costs (2020 GBP/USD/EUR/CHF) and utility values were sourced from published literature and AFFIRM-AHF. Modelled outcomes indicated that treatment with FCM was dominant (cost saving with additional health gains) in the UK, USA and Switzerland, and highly cost-effective in Italy [incremental cost-effectiveness ratio (ICER) EUR 1269 per quality-adjusted life-year (QALY)]. Results were driven by reduced costs for HHF events combined with QALY gains of 0.43-0.44, attributable to increased time in higher KCCQ states (representing better functional outcomes). Sensitivity and subgroup analyses demonstrated data robustness, with the ICER remaining dominant or highly cost-effective under a wide range of scenarios, including increasing treatment costs and various patient subgroups, despite a moderate increase in costs for de novo HF and smaller QALY gains for ischaemic aetiology. CONCLUSION Ferric carboxymaltose is estimated to be a highly cost-effective treatment across countries (Italy, UK, USA and Switzerland) representing different healthcare systems.
Granulomatosis With Polyangiitis and Microscopic Polyangiitis: A Systematic Review and Meta-Analysis of Benefits and Harms of Common Treatments
ACR open rheumatology. 2021
OBJECTIVE The aim of this systemic review is to compare different treatments for patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) to inform evidence-based recommendations for the American College of Rheumatology (ACR)/Vasculitis Foundation (VF) Vasculitis Management Guidelines. METHODS A systemic review was conducted by searching articles in English using OVID Medline, PubMed, Embase, and the Cochrane Library. Articles were screened for suitability in addressing PICO questions, with studies presenting the highest level of evidence given preference. RESULTS A total of 729 full-text articles addressing GPA and MPA PICO questions were reviewed. For remission induction, rituximab was shown to be noninferior to cyclophosphamide (CYC) (odds ratio [OR]: 1.55, moderate certainty of evidence). The addition of plasma exchange to induction therapy in severe disease did not improve the composite end point of death or end stage renal disease (hazard ratio [HR]: 0.86 [95% confidence interval CI: 0.65, 1.13], moderate certainty of evidence). In nonsevere disease, methotrexate was noninferior to CYC for induction of remission (remission at 6 months of 90% vs. 94%). For maintenance of remission, methotrexate and azathioprine showed no difference in the risk of relapse over a mean follow-up of 29 months (HR: 0.92, [95% CI: 0.52, 1.65]low certainty of evidence). As maintenance therapy, rituximab was superior to a tapering azathioprine strategy in major relapse-free survival at 28 months (HR: 6.61, [95% CI: 1.56, 27.96], moderate certainty of evidence). In two randomized trials, longer-term azathioprine maintenance therapy (>24 months) is associated with fewer relapses without an increase in adverse events. CONCLUSION This comprehensive systematic review synthesizes and evaluates the benefits and toxicities of different treatment options for GPA and MPA.
Dissolvable intranasal haemostatic agents for acute epistaxis: a systematic review and meta-analysis
Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2021
INTRODUCTION Nasal packing is the mainstay of epistaxis management; however, packs cause patient discomfort and can lead to hospital admission. Absorbable haemostats provide clotting factors or act as a substrate to stimulate clotting and represent a potential treatment alternative. A systematic review was performed to evaluate the efficacy of topical haemostats in the management of epistaxis. METHODS A systematic literature search of 7 databases was performed. Only eligible randomised controlled-trials (RCTs) and observational studies were included. The primary outcome was short-term haemostatic success (<7 days). Secondary outcomes included long-term haemostatic control (no re-bleeding 7-30 days), patient discomfort and adverse effects. Meta-analysis was performed where possible. RESULTS Of 2,249 records identified, 12 were included in the qualitative synthesis and 4 RCTs were included in meta-analysis. The following haemostats were reported: gelatin-thrombin matrix (n=8), aerosolised/gel tranexamic acid (n=1), cellulose agents (n=2), and fibrin sealants (n=1). Studies involving tranexamic acid on removable delivery devices (e.g. pledgets) were excluded. There was heterogeneity in outcome measures and inclusion criteria (coagulopathies/anticoagulants were excluded in 3 RCTs and 2 observational studies). The short-term haemostatic success varied between studies (13.9% to 100%). No significant post-procedural complications were reported. The meta-analysis favoured absorbable haemostatic agent versus packing (risk ratio 1.20; 95% confidence interval 1.05 to 1.37; p=0.007). The risk of bias across all studies was moderate to high. CONCLUSIONS The evidence suggests haemostatic agents are effective at managing acute epistaxis when compared with nasal packing. More data are required before recommendations can be made regarding management in patients on anticoagulants.
Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials
Annals of the American Thoracic Society. 2021
RATIONALE Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).
Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial
IMPORTANCE The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear. OBJECTIVE To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy. DESIGN, SETTING, AND PARTICIPANTS Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019. INTERVENTIONS Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy. MAIN OUTCOMES AND MEASURES The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome. RESULTS Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups. CONCLUSIONS AND RELEVANCE Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02648113.
Patients with myocardial infarction enrolled in the REALITY trial (n= 668).
Restrictive transfusion strategy, haemoglobin <8 g/dL (n= 342).
Liberal transfusion strategy, haemoglobin <10 g/dL (n = 324).
Among the patients in the restrictive transfusion group, 122 (35.7%) received transfusion, compared to 323 (99.7%) patients in the liberal transfusion group. At 30 days, major adverse cardiovascular events occurred in 36 patients (11.0%) in the restrictive group and in 45 patients (14.0%) in the liberal group. In the restrictive vs. liberal group, all-cause death occurred in 5.6% vs. 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs. 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs. 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups.
The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study
European heart journal. 2021
AIMS: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. METHODS AND RESULTS The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. CONCLUSION In iron-deficient patients with HF and left ventricular ejection fraction ≤50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.
Primary and Secondary Prevention Strategies for Gastrointestinal Bleeding in Patients with Left Ventricular Assist Device: A Systematic Review and Network Meta-analysis
Current problems in cardiology. 2021;:100835
Recurrent gastrointestinal bleeding (GIB) is a common complication following left ventricular assist device (LVAD) implantation. Our study aimed to estimate the comparative efficacy of different pharmacologic interventions for the prevention of GIB, through a network meta-analysis (NMA). A total of 13 observational studies comparing six strategies. Among those, 4 were for primary, and 9 were for secondary prevention of GIB. On NMA, thalidomide (Hazard ratio [HR]: 0.016, Credible interval [CrI]I: 0.00053-0.12), omega-3-fatty acid (HR:0.088, CrI: 0.026-0.77), octreotide (HR: 0.17, CrI: 0.0589-0.41) and danazol (HR:0.17, CrI: 0.059-0.41) reduced the risk of GIB. The use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker (ACEi/ARB) and digoxin were not associated with any significant reduction. Based on NMA, combining indirect treatment comparisons, thalidomide, danazol, and octreotide treatments were associated with decreased risk of recurrent GIB. Additionally, Omega 3 fatty acids were associated with a lower risk of the primary episode of GIB in the LVAD patient population.