Abstract

OBJECTIVE To assess the effects of plasma exchange on important outcomes in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). DESIGN Systematic review and meta-analysis of randomised controlled trials. ELIGIBILITY CRITERIA Randomised controlled trials investigating effects of plasma exchange in patients with AAV or pauci-immune rapidly progressive glomerulonephritis and at least 12 months' follow-up. INFORMATION SOURCES Prior systematic reviews, updated by searching Medline, Embase, and CENTRAL to July 2020. RISK OF BIAS Reviewers independently identified studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. SYNTHESIS OF RESULTS Meta-analyses were conducted using random effects models to calculate risk ratios and 95% confidence intervals. Quality of evidence was summarised in accordance with GRADE methods. Outcomes were assessed after at least12 months of follow-up and included all-cause mortality, end stage kidney disease (ESKD), serious infections, disease relapse, serious adverse events, and quality of life. RESULTS Nine trials including 1060 participants met eligibility criteria. There were no important effects of plasma exchange on all-cause mortality (relative risk 0.90 (95% CI 0.64 to 1.27), moderate certainty). Data from seven trials including 999 participants that reported ESKD demonstrated that plasma exchange reduced the risk of ESKD at 12 months (relative risk 0.62 (0.39 to 0.98), moderate certainty) with no evidence of subgroup effects. Data from four trials including 908 participants showed that plasma exchange increased the risk of serious infections at 12 months (relative risk 1.27 (1.08 to 1.49), moderate certainty). The effects of plasma exchange on other outcomes were uncertain or considered unimportant to patients. LIMITATIONS OF EVIDENCE There is a relative sparsity of events, and treatment effect estimates are therefore imprecise. Subgroup effects at the participant level could not be evaluated. INTERPRETATION For the treatment of AAV, plasma exchange has no important effect on mortality, reduces the 12 month risk of ESKD, but increases the risk of serious infections. FUNDING No funding was received. REGISTRATION This is an update of a previously unregistered systematic review and meta-analysis published in 2014.

Abstract

Introduction: Daprodustat, a novel hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), its efficacy and safety remain unclear. Thus, we conducted this meta-analysis aiming at investigating its efficacy and safety on the treatment of patients with chronic kidney disease (CKD)-related anemia. Methods: We systematically searched for relevant studies in PubMed, Embase, Cochrane Library and Clinical Trial Registries databases from inception until December 2021. We selected randomized controlled trials comparing daprodustat with recombinant human erythropoietin (rhEPO) in anemia patients with CKD with or without dialysis. Results: Seven studies including 7933 patients met the inclusion criteria. For both nondialysis-dependent (NDD-) CKD and dialysis-dependent (DD-) CKD patients, the pooled results showed that there was no significant difference in the changes in hemoglobin levels between the daprodustat and rhEPO groups (mean difference (MD) = -0.01, 95% confidence interval (CI) = -0.38, 0.35, p = 0.95; MD = 0.15, 95% CI = -0.29, 0.60, p = 0.50; respectively). In addition, a significant increase in transferrin saturation (TSAT), total iron binding capacity (TIBC) and total iron was observed in daprodustat groups compared with rhEPO groups in DD-CKD patients (p < 0.05). As for safety, the overall frequency of adverse events was similar between the daprodustat and rhEPO groups in DD-CKD patients (relative risk (RR) = 0.99, 95%CI = 0.92, 1.06, p = 0.76), and the trial sequential analysis (TSA) confirmed this result. But for NDD-CKD patients, the incidence of adverse events in the daprodustat groups was significantly higher than that of rhEPO groups (RR = 1.04, 95%CI = 1.01,1.07, p = 0.02), while the TSA corrected this result. No trend of increasing incidence of serious adverse events was found in all daprodustat treated patients, but the TSA could not confirm this result. Conclusion: Although daprodustat was noninferior to rhEPO in correcting anemia in both NDD-CKD and DD-CKD patients, it seemed to have a better effect on optimizing iron metabolism in DD-CKD patients. Daprodustat may be a promising alternative for the treatment of anemia in patients with CKD. However, due to the lack of included studies, future researches are needed to further evaluate the therapeutic effect of daprodustat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021229636.

Abstract

Heart failure (HF) patients with iron deficiency (ID) have worse NYHA class and are at a higher risk of recurrent hospitalizations. Intravenous (IV) iron has been shown to improve exercise ability and reduce hospitalizations. IV Sodium Ferric Gluconate Complex (SFGC) has been found to be safe and affordable but has not been studied in this population in a randomized trial. This was prospective, single-blind, investigator-initiated, randomized controlled trial. Patients admitted for acute heart failure with ID were randomly assigned 1:1 to receive IV SFGC on top of optimal medical treatment. The primary outcome was the change in 6-minute walk test (6MWT) from baseline to 3 and 6 months. Between September 2019 and May 2021, 34 patients were randomized. 19 patients (55%) were randomized to the treatment arm receiving 125 mg of IV SFGC per day for 3 to 5 days . COVID-19 was a major barrier to the implementation of the study follow-up protocol, which caused the study to end early. Both groups of patients had similar clinical characteristics, comorbidities, median LVEF, and rate of death and readmissions due to HF. A higher level of NT-proBNP was observed in patients treated with IV iron (7902 pg/ml vs 3158, p=0.04). There was no difference in 6MWT change between groups at 3 months (improvement of 21.6 vs 24.1 meters), or 6 months (-5 meters vs. 46 meters). In conclusion, IV SFGC treated patients had comparable 6-minute walk at 3 and 6 months despite suffering from more severe HF with higher baseline NT-Pro BNP. (NCT04063033).

Abstract

INTRODUCTION Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD). METHODS Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non-DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment. RESULTS In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point. CONCLUSION In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.

Abstract

AIM: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM vs placebo and evaluated the stability of this response over time. METHODS Changes vs baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups . Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed. RESULTS Overall, 760 (FCM: 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM vs 4.8 points with placebo (least-square mean difference [95% confidence interval (CI)]: 4.36 [2.14;6.59] points). A higher proportion of patients on FCM vs placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs 43.5%; odds ratio [95% CI]: 1.81 [1.30;2.51]), ≥10 (42.4% vs 29.3%; 1.73 [1.23;2.43]) or ≥15 (32.1% vs 22.6%; 1.46 [1.02;2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24. CONCLUSION Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).

Abstract

Antineutrophil cytoplasmic antibody-associated vasculitis has associations with both thrombosis and diffuse alveolar hemorrhage (DAH). Management of patients having coexistence of both thrombotic and hemorrhagic manifestations is challenging. Thrombotic conditions require anticoagulation, which can theoretically increase the risk of bleeding and thereby worsen DAH. In this review, we highlight the management of a patient of granulomatosis with polyangiitis with DAH who developed deep vein thrombosis. A systematic review of the literature was also performed summarizing and discussing the issues pertaining to the management of such patients.

Abstract

BACKGROUND The presence of esophageal varices is considered a relative contraindication to transesophageal echocardiography (TEE) by cardiology professional societies, so gastroenterologists are often consulted to perform upper endoscopy prior to TEE in patients with cirrhosis. AIM: To perform a systematic review to quantify the risk of bleeding complications in patients with cirrhosis following TEE. METHODS Two reviewers searched Ovid MEDLINE, MEDLINE In-Process and EMBASE databases from January 1992 to May 2021 for studies reporting bleeding complications from TEE in patients with cirrhosis. We calculated the pooled incidence rate of bleeding events using the metaprop command with a random effect model. RESULTS We identified 21 studies comprising 4050 unique patients with cirrhosis; 9 studies (n = 3015) assessed the risk of intraoperative TEE during liver transplant (LT) and 12 studies (n = 1035) assessed bleeding risk in patients undergoing TEE for other indications. The pooled incidence of bleeding post-TEE was 0.37% (95% CI 0.04-0.94%) across all studies. Bleeding complications were low among patients undergoing TEE during LT as well as those undergoing TEE for other diagnostic reasons (0.97% vs. 0.004%) and among studies with mean MELD >18 compared to those with mean MELD <18 (0.43% vs. 0.08%). Few studies had a comparator arm, and data on patient-level factors impacting bleeding complications (including degree of liver dysfunction and coagulopathy) were limited across studies. CONCLUSIONS The risk of bleeding complications following TEE is low in patients with cirrhosis, suggesting TEE is safe and risk stratification with upper endoscopy may not be necessary.

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a rare multisystem autoimmune condition that causes inflammation of small and medium-sized blood vessels and is more commonly seen in the geriatric population. ANCA-associated vasculitis (AAV) is typically characterized as necrotizing vasculitis and includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The mortality rate remains high, with especially cardiovascular disease, infections, and malignancies being the leading causes of death. Existing treatment options depend heavily on the use of glucocorticoids (GCs), often in combination with cyclophosphamide (CYC); however, as the multitude of adverse effects associated with these agents has increased, numerous studies are being conducted to reduce not only these harmful effects but also improve remission rates. Rituximab, avacopan, corticosteroids, including intravenous pulse methylprednisolone, plasma exchange, and immunological targeting are among the emerging treatments. The purpose of this review is to emphasize the pathogenesis and traditional treatment modalities and give insights into the recent advances in managing this disorder in an attempt to spare the adverse effects of conventional therapies while achieving better remission rates with combination therapies as well. The authors explored multiple databases, employing appropriate keywords, satisfying the quality appraisal, after which a total of 14 reports were included in this review. Upon overall analysis, it can be concluded that rituximab and CYC, when used in combination, provided a safer alternative to GCs while exhibiting equal, if not superior, effectiveness and results, thus, paving the way for additional in-depth research in a larger population of interest.

Abstract

BACKGROUND Anaemia is a common sequela of advanced disease and is associated with significant symptom burden. No specific guidance exists for the investigation and management of anaemia in palliative care patients. AIM: We aim to offer a pragmatic overview of the approaches to investigate and manage anaemia in advanced disease, based on guidelines and evidence in disease specific patient groups, including cancer, heart failure and chronic kidney disease. DESIGN Scoping review methodology was used to determine the strength of evidence supporting the investigation and management of anaemia in patients with advanced disease. DATA SOURCES A search for guidelines was performed in 2020. National or international guidelines were examined if they described the investigation or management of anaemia in adult patients with health conditions seen by palliative care services written within the last 5 years in the English language. Searches of MEDLINE, the Cochrane library and WHO guidance were made in 2019 to identify key publications that provided additional primary data. RESULTS Evidence supports patient-centred investigation of anaemia, results of which should guide targeted intervention. Blanket use of blood transfusion should be avoided, with evidence supporting a more restrictive approach to transfusion. Routine use of oral iron and erythropoetin stimulating agents (ESAs) are not recommended. Insufficient evidence exists to determine the effectiveness of IV iron in this patient group. CONCLUSION We advocate early consideration and investigation of anaemia, guided by symptom burden and patient preferences. Correction of reversible causes should be the mainstay of treatment, with a restrictive approach to blood transfusion. Research is required to evaluate the efficacy of IV iron in these patients.