Abstract

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.

Abstract

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.

Abstract

INTRODUCTION The optimal therapy for bleeding-related gastric varices is still a controversial topic. There is a paucity of literature that comprehensively summarizes the available literature regarding safety and efficacy of thrombin in bleeding gastric varices. METHODS Four independent reviewers performed a comprehensive review of all original articles published from inception to October 2020, describing the use of thrombin for management of bleeding gastric varices. Primary outcomes were (1) pooled early and late rebleeding rate, (2) pooled gastric variceal related mortality rate, (3) pooled rescue therapy rate, and (4) pooled adverse event rate with the use of thrombin in bleeding gastric varices. The meta-analysis was performed and the statistics were two-tailed. Finally, probability of publication bias was assessed using funnel plots and with Egger's test. RESULTS Eleven studies were included in the analysis after comprehensive search. This yielded a pooled early rebleeding rate of 9.3% (95% CI 4.9-17) and late rebleeding rate 13.8% (95% CI 9-20.4). Pooled rescue therapy rate after injecting thrombin in bleeding gastric varices was 10.1% (95% CI 6.1-16.3). The pooled 6-week gastric variceal-related mortality rate after injecting thrombin in bleeding gastric varices was 7.6% (95% CI 4.5-12.5). There were a total of four adverse events out of a total of 222 patients with pooled adverse event rate after injecting thrombin in bleeding gastric varices was 5.6% (95% CI 2.9-10.6). CONCLUSION In summary, the systematic review and meta-analysis on the use of thrombin for bleeding gastric varices suggest low rates of rebleeding and minimal rates of adverse events. While, early and late rebleeding rate and rescue therapy rate are similar to cyanoacrylate-based therapy, the minimal rates of adverse events are perhaps the most important benefit of thrombin. Thus, the current data suggest that thrombin is a very promising therapeutic alternative with low risk of adverse events for bleeding gastric varices.

Abstract

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.

Abstract

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.

Abstract

STUDY OBJECTIVE Epistaxis is a common emergency department (ED) presentation and, if simple first aid measures fail, can lead to a need for anterior nasal packing. Tranexamic acid is an agent that contributes to blood clot stability. The aim of this study is to investigate the effectiveness of topical intranasal tranexamic acid in adult patients presenting to the ED with persistent epistaxis, and whether it reduces the need for anterior nasal packing. METHODS From May 5, 2017, to March 31, 2019, a double-blind, placebo-controlled, multicenter, 1:1, randomized controlled trial was conducted across 26 EDs in the United Kingdom. Participants with spontaneous epistaxis, persisting after simple first aid and the application of a topical vasoconstrictor, were randomly allocated to receive topical tranexamic acid or placebo. The primary outcome was the need for anterior nasal packing of any kind during the index ED attendance. Secondary outcome measures included hospital admission, need for blood transfusion, recurrent epistaxis, and any thrombotic events requiring any hospital reattendance within 1 week. RESULTS The study sample consisted of 496 participants with spontaneous epistaxis, persisting after simple first aid and application of a topical vasoconstrictor. In total, 211 participants (42.5%) received anterior nasal packing during the index ED attendance, including 111 of 254 (43.7%) in the tranexamic acid group versus 100 of 242 (41.3%) in the placebo group. The difference was not statistically significant (odds ratio 1.107; 95% confidence interval 0.769 to 1.594; P=.59). Furthermore, there were no statistically significant differences between tranexamic acid and placebo for any of the secondary outcome measures. CONCLUSION In patients presenting to an ED with atraumatic epistaxis that is uncontrolled with simple first aid measures, topical tranexamic acid applied in the bleeding nostril on a cotton wool dental roll is no more effective than placebo at controlling bleeding and reducing the need for anterior nasal packing.

Abstract

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.

Abstract

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.

Abstract

BACKGROUND The effectiveness of oral and intravenous iron supplementation in reducing the risk of mortality and hospitalizations in HF patients with iron deficiency is not well-established. METHODS A thorough literature search was conducted across 2 electronic databases (Medline and Cochrane Central) from inception through March 2021. RCTs assessing the impact of iron supplementation on clinical outcomes in iron deficient HF patients were considered for inclusion. Primary end-points included all-cause mortality and HF hospitalization. Evaluations were reported as odds ratios (ORs) or risk ratios (RRs) with 95% confidence intervals (CI) and analysis was performed using a random effects model. I(2) index was used to assess heterogeneity. RESULTS From the 2599 articles retrieved from initial search, 10 potentially relevant studies (n = 2187 patients) were included in the final analysis. Both oral (OR: 0.93; 95% CI: 0.08-11.30; p = 0.951) and intravenous (OR: 0.97; 95% CI: 0.73-1.29; p = 0.840) iron supplementation did not significantly reduce all-cause mortality. However, intravenous iron supplementation significantly decreased the rates of overall (OR: 0.52; 95% CI: 0.33-0.81; p = 0.004) and HF (OR: 0.42; 95% CI: 0.22-0.80; p = 0.009) hospitalizations. In addition, intravenous ferric carboxymaltose therapy significantly reduced the time to first HF hospitalization or cardiovascular mortality (RR = 0.70; 95% CI = 0.50-1.00; p = 0.048), but had no effect on time to first cardiovascular death (RR: 0.94; 95% CI: 0.70-1.25; p = 0.655). CONCLUSION Oral or intravenous iron supplementation did not reduce mortality in iron deficient HF patients. However, intravenous iron supplementation was associated with a significant decrease in overall and HF hospitalizations.

Abstract

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.