Heart failure events in randomized controlled trials for adults receiving maintenance dialysis: a meta-epidemiologic study.

BACKGROUND AND HYPOTHESIS: Heart failure is characterized as cardiac dysfunction resulting in elevated cardiac filling pressures with symptoms and signs of congestion. Distinguishing heart failure from other causes of similar presentations in patients with kidney failure is challenging but necessary, and is needed in randomized controlled trials (RCTs) to accurately estimate treatment effects. The objective of this study was to review heart failure events, their diagnostic criteria and adjudication in RCTs of patients with kidney failure treated with dialysis. We hypothesized that heart failure events, diagnostic criteria and adjudication were infrequently reported in RCTs in dialysis. METHODS: We conducted a meta-epidemiologic systematic review of RCTs from high impact medical, nephrology and cardiology journals from 2000 to 2020. RCTs were eligible if they enrolled adults receiving maintenance dialysis for kidney failure and evaluated any intervention. Results. Of 561 RCTs in patients receiving dialysis, 36 (6.4%) reported heart failure events as primary (10, 27.8%) or secondary (31, 86.1%) outcomes. 10 of the 36 (27.8%) RCTs provided heart failure event diagnostic criteria and 5 of these 10 (50%) adjudicated heart failure events. These 10 RCTs included event diagnostic criteria for heart failure or heart failure hospitalizations, and their criteria included dyspnea (5/10), edema (2/10), rales/crackles (4/10), chest x-ray pulmonary edema or vascular redistribution (4/10), treatment in an acute setting (6/10) and ultrafiltration or dialysis (4/10). No study explicitly distinguished heart failure from volume overload secondary to non-adherence or underdialysis. CONCLUSION: Overall, we found that heart failure events are infrequently reported in RCTs in dialysis and are heterogeneously defined. Further research is required to develop standardized diagnostic criteria that are practical and meaningful to patients and clinicians.

Sex and Gender in Randomized Controlled Trials of Adults Receiving Maintenance Dialysis: A Meta-epidemiologic Study.

RATIONALE & OBJECTIVE: How sex and gender concepts are incorporated into randomized controlled trials (RCTs) in adults with kidney failure receiving maintenance dialysis is largely unknown. We describe these practices in published journal articles as well as investigate the proportion of women and female participants in these studies. STUDY DESIGN: Meta-epidemiologic study. SETTING & STUDY POPULATIONS: RCTs in maintenance dialysis. SELECTION CRITERIA FOR STUDIES: Trials published in high-impact journals in 2000-2020. DATA EXTRACTION: Implemented in duplicate with conflicts resolved by a third reviewer. ANALYTICAL APPROACH: Meta-regression was performed to identify trial characteristics independently associated with the proportion of women and female participants. RESULTS: Among 561 included RCTs, 69.7% were parallel and 28.0% were crossover in design; 80.6% were conducted in the hemodialysis population; and 25% of trials compared the treatment of interest with a placebo arm, 25% with a usual care treatment arm, and 50% with an active alternative therapy arm. Of the RCTS, 37.6% were masked. The median size was 60 (IQR, 26-151) participants, and the median follow-up period was 154 (IQR, 42-365) days. The mean proportion of women or female participants was 0.40±0.13 (SD): 39.0% of trials reported sex, and 26.6% reported the gender of the participants. Also, 56.2% referred to participants as females, 25.3% referred to participants as women, and 15.5% referred to both females and women. No trial characteristic other than region (ß of 0.062 [95% CI, 0.007-0.117] for Asia) was associated with the proportion of women or female participants. Considering trial design and conduct, 2.7% of trials used sex and/or gender as an inclusion criterion, 26.6% as an exclusion criterion, 4.5% for randomization, 4.8% for subgroup analyses, and 15.7% for covariate adjustment. LIMITATIONS: Only high-impact journal articles were studied; and the included studies lacked pediatric trials, those addressing chronic kidney disease or kidney transplantation, any trials from Africa and underrepresentation of other regions, and missing data. CONCLUSIONS: RCTs in dialysis are representative of the general dialysis population with regard to sex and gender but they uncommonly report both and often do not include either in their reporting or analysis.

Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis.

BACKGROUND: Atopic dermatitis is a prevalent condition in children and can be effectively managed with medications such as topical calcineurin inhibitors (pimecrolimus or tacrolimus). A key unresolved safety concern is whether use of topical calcineurin inhibitors is associated with cancer. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors. METHODS: As part of the 2022 American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters atopic dermatitis guidelines, we searched MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature database, the Índice Bibliográfico Espanhol de Ciências da Saúde database, the Global Resource of Eczema Trials database, WHO's International Clinical Trials Registry Platform, the US Food and Drug Administration database, the European Medicines Agency database, company registers, and relevant citations from inception to June 6, 2022. We included randomised controlled trials and comparative and non-comparative non-randomised studies in any language addressing cancer risk in patients with atopic dermatitis using topical calcineurin inhibitors. We excluded split-body studies and studies with less than 3 weeks of follow-up. Paired reviewers independently screened records, extracted data, and assessed risk of bias in duplicate. We used Bayesian models to estimate the probability for cancer due to topical calcineurin inhibitor exposure and the GRADE approach to determine the certainty of the evidence. Patients, advocacy groups, and care providers set a priori thresholds of important effects. This study is registered with Open Science Framework, https://osf.io/v4bfc. FINDINGS: We identified and analysed 110 unique studies (52 randomised controlled trials and 69 non-randomised studies [11 were non-randomised study extensions of randomised controlled trials]) including 3·4 million patients followed up for a mean of 11 months (range 0·7-120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was not different from controls (absolute risk 4·70 per 1000 with topical calcineurin inhibitors vs 4·56 per 1000 without; odds ratio 1·03 [95% credible interval 0·94-1·11]; moderate certainty). For all age groups and using data from observational studies and randomised controlled trials, the use of pimecrolimus (OR 1·05 [95% credible interval 0·94-1·15]) or tacrolimus (0·99 [0·89-1·09]) is likely to have had little to no association with cancer compared with no topical calcineurin inhibitor exposure. For pimecrolimus versus tacrolimus, the finding was similar (0·95 [95% credible interval 0·83-1·07]). Findings were similar in infants, children, and adults, and robust to trial sequential, subgroup, and sensitivity analyses. INTERPRETATION: Among individuals with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the optimal treatment of patients with atopic dermatitis. FUNDING: American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology via the Joint Task Force on Practice Parameters.

Comparing Renal Replacement Therapy Modalities in Critically Ill Patients With Acute Kidney Injury: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: To compare different modalities of renal replacement therapy in critically ill adults with acute kidney injury. DATA SOURCES: We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 25 May, 2020. We included randomized controlled trials comparing the efficacy and safety of different renal replacement therapy modalities in critically ill patients with acute kidney injury. STUDY SELECTION: Ten reviewers (working in pairs) independently screened studies for eligibility, extracted data, and assessed risk of bias. DATA EXTRACTION: We performed random-effects frequentist network meta-analyses and used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess certainty of evidence. The primary analysis was a four-node analysis: continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and peritoneal dialysis. The secondary analysis subdivided these four nodes into nine nodes including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, continuous veno-venous hemodiafiltration, continuous arterio-venous hemodiafiltration, intermittent hemodialysis, intermittent hemodialysis with hemofiltration, slow efficiency extended dialysis, slow efficiency extended dialysis with hemofiltration, and peritoneal dialysis. We set the minimal important difference threshold for mortality as 2.5% (relative difference, 0.04). DATA SYNTHESIS: Thirty randomized controlled trials (n = 3,774 patients) proved eligible. There may be no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis (relative risk, 1.04; 95% CI, 0.93-1.18; low certainty), whereas continuous renal replacement therapy demonstrated a possible increase in mortality compared with slow efficiency extended dialysis (relative risk, 1.06; 95% CI, 0.85-1.33; low certainty) and peritoneal dialysis (relative risk, 1.16; 95% CI, 0.92-1.49; low certainty). Continuous renal replacement therapy may increase renal recovery compared with intermittent hemodialysis (relative risk, 1.15; 95% CI, 0.91-1.45; low certainty), whereas both continuous renal replacement therapy and intermittent hemodialysis may be worse for renal recovery compared with slow efficiency extended dialysis and peritoneal dialysis (low certainty). Peritoneal dialysis was probably associated with the shortest duration of renal support and length of ICU stay compared with other interventions (low certainty for most comparisons). Slow efficiency extended dialysis may be associated with shortest length of hospital stay (low or moderate certainty for all comparisons) and days of mechanical ventilation (low certainty for all comparisons) compared with other interventions. There was no difference between continuous renal replacement therapy and intermittent hemodialysis in terms of hypotension (relative risk, 0.92; 95% CI, 0.72-1.16; moderate certainty) or other complications of therapy, but an increased risk of hypotension and bleeding was seen with both modalities compared with peritoneal dialysis (low or moderate certainty). Complications of slow efficiency extended dialysis were not sufficiently reported to inform comparisons. CONCLUSIONS: The results of this network meta-analysis suggest there is no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis although continuous renal replacement therapy may increases renal recovery compared with intermittent hemodialysis. Slow efficiency extended dialysis with hemofiltration may be the most effective intervention at reducing mortality. Peritoneal dialysis is associated with good efficacy, and the least number of complications however may not be practical in all settings. Importantly, all conclusions are based on very low to moderate certainty evidence, limited by imprecision. At the very least, ICU clinicians should feel comfortable that the differences between continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and, where clinically appropriate, peritoneal dialysis are likely small, and any of these modalities is a reasonable option to employ in critically ill patients.

Multidisciplinary Chronic Kidney Disease Clinic Practices: A Scoping Review.

BACKGROUND: Multidisciplinary chronic kidney disease (CKD) clinics improve patient outcomes but their optimal design is unclear. OBJECTIVE: To perform a scoping review to identify and describe current practices (structure, function) associated with multidisciplinary CKD clinics. DESIGN: Scoping review. SETTING: Databases included Medline, EMBASE, Cochrane, and CINAHL. PATIENTS: Patients followed in multidisciplinary CKD clinics globally. MEASUREMENTS: Multidisciplinary CKD clinic composition, entry criteria, follow-up, and outcomes. METHODS: We systematically searched the literature to identify randomized controlled trials, non-randomized interventional studies, or observational studies of multidisciplinary CKD clinics defined by an outpatient setting where two or more allied health members (with or without a nephrologist) provided longitudinal care to 50 or more adult or pediatric patients with CKD. Included studies were from 2002 to present. Searches were completed on August 10, 2018. Title, abstracts, and full texts were screened independently by two reviewers with disagreements resolved by a third. We abstracted data from included studies to summarize multidisciplinary CKD clinic team composition, entry criteria, follow-up, and processes. RESULTS: 40 studies (8 randomized controlled trials and 32 non-randomized interventional studies or observational studies) involving 23 230 individuals receiving multidisciplinary CKD care in 12 countries were included. Thirty-eight focused on adults (27 with CKD, 10 incident dialysis patients, one conservative therapy) while two studies focused on adolescents or children with CKD. The multidisciplinary team included a mean of 4.6 (SD 1.5) members consisting of a nephrologist, nurse, dietician, social worker, and pharmacist in 97.4%, 86.8%, 84.2%, 57.9%, and 42.1% of studies respectively. Entry criteria to multidisciplinary CKD clinics ranged from glomerular filtration rates of 20 to 70 mL/min/1.73m2 or CKD stages 1 to 5 without any proteinuria or risk equation-based criteria. Frequency of follow-up was variable by severity of kidney disease. Team member roles and standardized operating procedures were infrequently reported. LIMITATIONS: Unstandardized definition of multidisciplinary CKD care, studies limited to CKD defined by glomerular filtration rate, and lack of representation from countries other than Canada, Taiwan, the United States, and the United Kingdom. CONCLUSIONS: There is heterogeneity in multidisciplinary CKD team composition, entry criteria, follow-up, and processes with inadequate reporting of this complex intervention. Additional research is needed to determine the best model for multidisciplinary CKD clinics. TRIAL REGISTRATION: Not applicable.

CONTEXTE: Les cliniques multidisciplinaires d'insuffisance rénale chronique (cliniques d'IRC) permettent d'améliorer les issues des patients, mais le modèle optimal demeure inconnu. OBJECTIFS: Procéder à un examen exploratoire pour répertorier et décrire les pratiques actuelles (structure, fonction) des cliniques d'IRC. TYPE D'ÉTUDE: Revue exploratoire. SOURCES: Les bases de données Medline, EMBASE, Cochrane et CINAHL. SUJETS: Les patients suivis en cliniques d'IRC partout dans le monde. MESURES: La composition de la clinique, les critères d'admission, le suivi et les résultats. MÉTHODOLOGIE: Nous avons parcouru la littérature de façon systématique et répertorié les essais contrôlés à répartition aléatoire, les études interventionnelles non réparties aléatoirement ou les études observationnelles portant sur des cliniques d'IRC. Ces dernières étaient définies par un contexte de consultations externes où au moins deux fournisseurs de soins connexes (avec ou sans néphrologue) ont fourni des soins longitudinaux à au moins 50 patients, adultes ou enfants, atteints d'IRC. Les études incluses dataient de 2002 à aujourd'hui. La recherche s'est terminée le 10 août 2018. Deux réviseurs ont, de façon indépendante, passé en revue le titre, le résumé et l'article complet. Les désaccords ont été résolus par une tierce personne. La composition de l'équipe, les critères d'admission, le suivi et les processus de la clinique ont été déterminés à partir des données extraites des études retenues. RÉSULTATS: Ont été retenues 40 études (8 essais contrôlés à répartition aléatoire et 32 études interventionnelles non aléatoires ou études observationnelles) touchant 23 230 individus recevant des soins multidisciplinaires en IRC dans 12 pays différents. Trente-huit études portaient sur des adultes (patients atteints d'IRC [n=27], patients dialysés incidents [n=10] et patients ayant un traitement conservateur [n=1]). Les deux autres portaient sur des adolescents ou des enfants atteints d'IRC. L'équipe multidisciplinaire comptait en moyenne 4,6 (écart-type: 1,5) membres, dont un néphrologue, une infirmière, un diététiste, un travailleur social et un pharmacien (97,4 %, 86,8 %, 84,2 %, 57,9 % et 42,1 % des études, respectivement). Les critères d'admission à la clinique consistaient en un débit de filtration glomérulaire de 20 à 70 ml/min/1,73 m2, une IRC de stade 1 à 5 sans protéinurie ou des critères de risque fondés sur des équations. La fréquence des suivis variait selon la gravité de l'atteinte rénale. Les rôles des membres de l'équipe et les procédures opérationnelles standardisées étaient rarement discutés. LIMITES: Les résultats sont limités par une définition non standardisée de « soins multidisciplinaires en IRC ¼ et le manque de représentation de pays autres que le Canada, Taiwan, les États-Unis et le Royaume-Uni. De plus, les études retenues étaient limitées par une définition de l'IRC reposant sur le débit de filtration glomérulaire. CONCLUSION: On observe une hétérogénéité dans la composition des équipes multidisciplinaires des cliniques d'IRC. Les critères d'admission, le suivi et les procédures sont également divergents, et les rapports sur cette intervention complexe sont inadéquats. D'autres études sont nécessaires pour définir le meilleur modèle de clinique multidisciplinaire en IRC.

Increasing treatment in early rheumatoid arthritis is not determined by the disease activity score but by physician global assessment: results from the CATCH study.

OBJECTIVE: To determine the factors most strongly associated with an increase in therapy of early rheumatoid arthritis (ERA). METHODS: Data from the Canadian Early Arthritis Cohort (CATCH) were included if the patient had ≥ 2 visits and baseline and 6 months data. A regression analysis was done to determine factors associated with treatment intensification. RESULTS: Of 1145 patients with ERA, 790 met inclusion criteria; mean age was 53.4 years (SD 14.7), mean disease duration 6.1 months (SD 2.8), 75% were female, baseline Disease Activity Score-28 (DAS28) was 4.7 (SD 1.8) and 2.9 (SD 1.8) at 6 months for included patients. Univariate factors for intensifying treatment were physician global assessment (MDGA; OR 7.8 and OR 7.4 at 3 and 6 months, respectively, p < 0.0005), swollen joint count (SJC; OR 4.7 and OR 7.3 at 3 and 6 months, p < 0.0005), and DAS28 (OR 3.0 and OR 4.6 at 3 and 6 months, p < 0.0005). In the regression model only MDGA was strongly associated with treatment intensification (OR 1.5 and OR 1.2 at 3 and 6 months, p < 0.0005); DAS28 was not consistently predictive (OR 1.0, p = 0.987, and OR 1.2, p = 0.023, at 3 and 6 months). DAS28 was the reason for treatment intensification 2.3% of the time, compared to 51.7% for SJC, 49.9% for tender joint count, and 23.8% for MDGA. For the same SJC, larger joint involvement was more likely to influence treatment than small joints at 3 months (OR 1.4, p = 0.027). CONCLUSION: MDGA was strongly associated with an increase in treatment at 3 and 6 months in ERA, whereas DAS28 was not. Physicians rarely stated that DAS28 was the reason for increasing treatment.