Virtual Care Team Guided Management of Patients With Heart Failure During Hospitalization.

BACKGROUND: Scalable and safe approaches for heart failure guideline-directed medical therapy (GDMT) optimization are needed. OBJECTIVES: The authors assessed the safety and effectiveness of a virtual care team guided strategy on GDMT optimization in hospitalized patients with heart failure with reduced ejection fraction (HFrEF). METHODS: In a multicenter implementation trial, we allocated 252 hospital encounters in patients with left ventricular ejection fraction ≤40% to a virtual care team guided strategy (107 encounters among 83 patients) or usual care (145 encounters among 115 patients) across 3 centers in an integrated health system. In the virtual care team group, clinicians received up to 1 daily GDMT optimization suggestion from a physician-pharmacist team. The primary effectiveness outcome was in-hospital change in GDMT optimization score (+2 initiations, +1 dose up-titrations, -1 dose down-titrations, -2 discontinuations summed across classes). In-hospital safety outcomes were adjudicated by an independent clinical events committee. RESULTS: Among 252 encounters, the mean age was 69 ± 14 years, 85 (34%) were women, 35 (14%) were Black, and 43 (17%) were Hispanic. The virtual care team strategy significantly improved GDMT optimization scores vs usual care (adjusted difference: +1.2; 95% CI: 0.7-1.8; P < 0.001). New initiations (44% vs 23%; absolute difference: +21%; P = 0.001) and net intensifications (44% vs 24%; absolute difference: +20%; P = 0.002) during hospitalization were higher in the virtual care team group, translating to a number needed to intervene of 5 encounters. Overall, 23 (21%) in the virtual care team group and 40 (28%) in usual care experienced 1 or more adverse events (P = 0.30). Acute kidney injury, bradycardia, hypotension, hyperkalemia, and hospital length of stay were similar between groups. CONCLUSIONS: Among patients hospitalized with HFrEF, a virtual care team guided strategy for GDMT optimization was safe and improved GDMT across multiple hospitals in an integrated health system. Virtual teams represent a centralized and scalable approach to optimize GDMT.

The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A systematic review.

BACKGROUND: The evidence for vitamin D and other agents that experimentally modulate T regulatory cells (Tregs) for the treatment of patients with autoimmune or allergic diseases has not been established. OBJECTIVE: We have undertaken a systematic review of randomised controlled trials to assess the efficacy of vitamin D, vitamin A, niacin and short-chain fatty acids in enhancing absolute Treg numbers and phenotypes in patients with inflammatory or autoimmune disease. METHODS: This systematic review was conducted using a predefined protocol (PROSPERO International prospective register of systematic reviews, ID = CRD42016048648/ CRD42016048646). Randomised controlled trials of patients with inflammatory or autoimmune disease or healthy participants which compared either oral vitamin D or vitamin A or short-chain fatty acids with control or placebo and measured the absolute concentration of proportion of Tregs were eligible for inclusion. Searches of electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, PUBMED and Web of Science) identified eight eligible independent trials (seven autoimmune disease trials, one trial of healthy subjects). Data were extracted by two reviewers and the risk of study bias was assessed using Cochrane Collaboration methodology. RESULTS: Planned meta-analysis was not possible due to the heterogeneous nature of the studies. Nevertheless, in five trials of autoimmune disorders which measured the proportion of Tregs, a higher proportion was observed in the vitamin D group compared to controls at 12 months in all but one trial. In the trial of healthy subjects, a significant difference was reported, with a higher percentage of Tregs observed in the vitamin D group (at 12 weeks, mean 6.4% (SD 0.8%) (vitamin D) vs 5.5% (1.0%) (placebo). There were no trials to assess the efficacy of vitamin A, niacin and short-chain fatty acids in enhancing absolute Treg numbers. CONCLUSIONS: Vitamin D supplementation may increase Treg/CD3 ratios in both healthy individuals and patients with autoimmune disorders and may increase Treg function. There remains a need for further suitably powered clinical studies aimed at enhancing Treg numbers and/or function.

Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors.

BACKGROUND: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. METHODS: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. FINDINGS: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7-1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04-0·17; p=0·0003) in men and 0·06 units per year (0·01-0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21-0·25) in men and 0·14 units per year (0·12-0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15-1·22] in men and 1·10 [1·06-1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval -0·84 g/L [95% CI -0·99 to -0·70] in men and -0·45 g/L [-0·59 to -0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval -6·5% [95% CI -7·6 to -5·5] in men and -5·3% [-6·5 to -4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001). INTERPRETATION: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. FUNDING: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.

Oral or parenteral iron supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors.

BACKGROUND: Iron deficiency is a significant cause of deferral in people wishing to donate blood. If iron removed from the body through blood donation is not replaced, then donors may become iron deficient. All donors are screened at each visit for low haemoglobin (Hb) levels. However, some deferred blood donors do not return to donate. Deferred first-time donors are even less likely to return. Interventions that reduce the risk of provoking iron deficiency and anaemia in blood donors will therefore increase the number of blood donations. Currently, iron supplementation for blood donors is not a standard of care in many blood services. A systematic review is required to answer specific questions regarding the efficacy and safety of iron supplementation in blood donors. OBJECTIVES: To assess the efficacy and safety of iron supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors. SEARCH METHODS: We ran the search on 18 November 2013. We searched Cochrane Injuries Group Specialised Register, CENTRAL, PubMed, MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO Host) and six other databases. We also searched clinical trials registers and screened guidelines reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing iron supplementation versus placebo or control, oral versus parenteral iron supplementation, iron supplementation versus iron-rich food supplements, and different doses, treatment durations and preparations of iron supplementation in healthy blood donors. Autologous blood donors were excluded. DATA COLLECTION AND ANALYSIS: We combined data using random-effects meta-analyses. We evaluated heterogeneity using the I(2) statistic; we explored considerable heterogeneity (I(2) > 75%) in subgroup analyses. We carried out sensitivity analyses to assess the impact of trial quality on the results. MAIN RESULTS: Thirty RCTs (4704 participants) met the eligibility criteria, including 19 comparisons of iron supplementation and placebo or control; one comparison of oral and parenteral iron supplementation; four comparisons of different doses of iron supplementation; one comparison of different treatment durations of iron supplementation; and 12 comparisons of different iron supplementation preparations.Many studies were of low or uncertain methodological quality and therefore at high or uncertain risk of bias. We therefore rated the quality of the evidence for our outcomes as moderate. There was a statistically significant reduction in deferral due to low haemoglobin in donors who received iron supplementation compared with donors who received no iron supplementation, both at the first donation visit after commencement of iron supplementation (risk ratio (RR) 0.34; 95% confidence interval (CI) 0.21 to 0.55; four studies; 1194 participants; P value < 0.0001) and at subsequent donations (RR 0.25; 95% CI 0.15 to 0.41; three studies; 793 participants; P value < 0.00001). Supplementation also resulted in significantly higher haemoglobin levels (mean difference (MD) 2.36 g/L; 95% CI 0.06 to 4.66; eight studies; 847 participants, P value =0.04), and iron stores, including serum ferritin (MD 13.98 ng/mL; 95% CI 8.92 to 19.03; five studies; 640 participants; P value < 0.00001) and transferrin saturation (MD 3.91%; 95% CI 2.02 to 5.80; four studies; 344 participants; P value < 0.0001) prior to further donation. The differences were maintained after subsequent donation(s).Adverse effects were widely reported and were more frequent in donors who received iron supplementation (RR 1.60; 95% CI 1.23 to 2.07; four studies; 1748 participants; P value = 0.0005). Adverse effects included constipation, diarrhoea, nausea, vomiting and taste disturbances, and some participants stopped treatment due to side effects. AUTHORS' CONCLUSIONS: There is moderate quality evidence that rates of donor deferral due to low haemoglobin are considerably less in those taking iron supplements compared with those without iron supplementation, both at the first donation visit and at subsequent donation. Iron-supplemented donors also show elevated haemoglobin and iron stores. These beneficial effects are balanced by more frequent adverse events in donors who receive iron supplementation than in those who do not; this is likely to limit acceptability and compliance. The long-term effects of iron supplementation without measurement of iron stores are unknown. These considerations are likely to preclude widespread use of iron supplementation by tablets. Blood services may consider targeted use of supplementation in those at greatest risk of iron deficiency, personalised donation intervals and providing dietary advice.

Oral deferiprone for iron chelation in people with thalassaemia.

BACKGROUND: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. OBJECTIVES: To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone with desferrioxamine for thalassaemia. SEARCH METHODS: We searched the Cochrane Cystic fibrosis and Genetic Disorders Group's Haemoglobinopathies trials Register and MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus registers of ongoing trials and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). We also contacted the manufacturers of deferiprone and desferrioxamine.All searches were updated to 05 March 2013. SELECTION CRITERIA: Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules or doses of deferiprone, in people with transfusion-dependent thalassaemia. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for risk of bias and extracted data. Missing data were requested from the original investigators. MAIN RESULTS: A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials.Four trials reported mortality; each reported the death of one individual receiving deferiprone with or without desferrioxamine. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage.Earlier trials measuring the cardiac iron load indirectly by magnetic resonance imaging (MRI) T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, a meta-analysis of two trials suggested that left ventricular ejection fraction was significantly reduced in patients who received desferrioxamine alone compared with combination therapy.  One trial, which planned five years of follow up, was stopped early due to the beneficial effects of combined treatment compared with deferiprone alone in terms of serum ferritin levels reduction.The results of this and three other trials suggest an advantage of combined therapy over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no conclusive or consistent evidence for the improved efficacy of combined deferiprone and desferrioxamine therapy over monotherapy from direct or indirect measures of liver iron. Both deferiprone and desferrioxamine produce a significant reduction in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised controlled trials to suggest that either has a greater reduction of clinically significant end organ damage.Evidence of adverse events were observed in all treatment groups. Occurrence of any adverse event was significantly more likely with deferiprone than desferrioxamine in one trial, RR 2.24 (95% CI 1.19 to 4.23). Meta-analysis of a further two trials showed a significant increased risk of adverse events associated with combined deferiprone and desferrioxamine compared with desferrioxamine alone, RR 3.04 (95% CI 1.18 to 7.83). The most commonly reported adverse event was joint pain, which occurred significantly more frequently in patients receiving deferiprone than desferrioxamine, RR 2.64 (95% CI 1.21 to 5.77). Other common adverse events included gastrointestinal disturbances as well as neutropenia or leucopenia, or both. AUTHORS' CONCLUSIONS: In the absence of data from randomised controlled trials, there is no evidence to suggest the need for a change in current treatment recommendations; namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. Intensified desferrioxamine treatment (by either subcutaneous or intravenous route) or use of other oral iron chelators, or both, remains the established treatment to reverse cardiac dysfunction due to iron overload. Indeed, the US Food and Drug Administration (FDA) recently only gave support for deferiprone to be used as a last resort for treating iron overload in thalassaemia, myelodysplasia and sickle cell disease. However, there is evidence that adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia.

BACKGROUND: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. Desferrioxamine mesylate (desferrioxamine) is one of the most widely used iron chelators. Substantial data have shown the beneficial effects of desferrioxamine, although adherence to desferrioxamine therapy is a challenge. Alternative oral iron chelators, deferiprone and deferasirox, are now commonly used. Important questions exist about whether desferrioxamine, as monotherapy or in combination with an oral iron chelator, is the best treatment for iron chelation therapy. OBJECTIVES: To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion-dependent thalassaemia.To summarise data from trials on the clinical efficacy and safety of desferrioxamine for thalassaemia and to compare these with deferiprone and deferasirox. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus ongoing trials registers and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). All searches were updated to 5 March 2013. SELECTION CRITERIA: Randomised controlled trials comparing desferrioxamine with placebo, with another iron chelator, or comparing two schedules or doses of desferrioxamine, in people with transfusion-dependent thalassaemia. DATA COLLECTION AND ANALYSIS: Six authors working independently were involved in trial quality assessment and data extraction. For one trial, investigators supplied additional data upon request. MAIN RESULTS: A total of 22 trials involving 2187 participants (range 11 to 586 people) were included. These trials included eight comparisons between desferrioxamine alone and deferiprone alone; five comparisons between desferrioxamine combined with deferiprone and deferiprone alone; eight comparisons between desferrioxamine alone and desferrioxamine combined with deferiprone; two comparisons of desferrioxamine with deferasirox; and two comparisons of different routes of desferrioxamine administration (bolus versus continuous infusion). Overall, few trials measured the same or long-term outcomes. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage; none of these included a comparison with deferasirox.Five trials reported a total of seven deaths; three in patients who received desferrioxamine alone, two in patients who received desferrioxamine and deferiprone. A further death occurred in a patient who received deferiprone in another who received deferasirox alone. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone.One trial planned five years of follow up but was stopped early due to the beneficial effects of a reduction in serum ferritin levels in those receiving combined desferrioxamine and deferiprone treatment compared with deferiprone alone. The results of this and three other trials suggest an advantage of combined therapy with desferrioxamine and deferiprone over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no evidence for the improved efficacy of combined desferrioxamine and deferiprone therapy against monotherapy from direct or indirect measures of liver iron.Earlier trials measuring the cardiac iron load indirectly by measurement of the magnetic resonance imaging T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, meta-analysis of two trials showed a significantly lower left ventricular ejection fraction in patients who received desferrioxamine alone compared with those who received combination therapy using desferrioxamine with deferiprone.Adverse events were recorded by 18 trials. These occurred with all treatments, but were significantly less likely with desferrioxamine than deferiprone in one trial, relative risk 0.45 (95% confidence interval 0.24 to 0.84) and significantly less likely with desferrioxamine alone than desferrioxamine combined with deferiprone in two other trials, relative risk 0.33 (95% confidence interval 0.13 to 0.84). In particular, four studies reported permanent treatment withdrawal due to adverse events from deferiprone; only one of these reported permanent withdrawals associated with desferrioxamine. Adverse events also occurred at a higher frequency in patients who received deferasirox than desferrioxamine in one trial. Eight trials reported local adverse reactions at the site of desferrioxamine infusion including pain and swelling. Adverse events associated with deferiprone included joint pain, gastrointestinal disturbance, increases in liver enzymes and neutropenia; adverse events associated with deferasirox comprised increases in liver enzymes and renal impairment. Regular monitoring of white cell counts has been recommended for deferiprone and monitoring of liver and renal function for deferasirox.In summary, desferrioxamine and the oral iron chelators deferiprone and deferasirox produce significant reductions in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised clinical trials to suggest that any one of these has a greater reduction of clinically significant end organ damage, although in two trials, combination therapy with desferrioxamine and deferiprone showed a greater improvement in left ventricular ejection fraction than desferrioxamine used alone. AUTHORS' CONCLUSIONS: Desferrioxamine is the recommended first-line therapy for iron overload in people with thalassaemia major and deferiprone or deferasirox are indicated for treating iron overload when desferrioxamine is contraindicated or inadequate. Oral deferasirox has been licensed for use in children aged over six years who receive frequent blood transfusions and in children aged two to five years who receive infrequent blood transfusions. In the absence of randomised controlled trials with long-term follow up, there is no compelling evidence to change this conclusion.Worsening iron deposition in the myocardium in patients receiving desferrioxamine alone would suggest a change of therapy by intensification of desferrioxamine treatment or the use of desferrioxamine and deferiprone combination therapy.Adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. People treated with all chelators must be kept under close medical supervision and treatment with deferiprone or deferasirox requires regular monitoring of neutrophil counts or renal function respectively. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcomes of deferiprone, deferasirox and desferrioxamine.

Hepcidin demonstrates a biphasic association with anemia in acute Plasmodium falciparum malaria.

Hepcidin levels are high and iron absorption is limited in acute malaria. The mechanism(s) that regulate hepcidin secretion remain undefined. We have measured hepcidin concentration and cytokines in 100 Kenyan children with acute falciparum malaria and different degrees of anemia. Hepcidin was increased on admission and fell significantly one week and one month after treatment. The association of hepcidin with hemoglobin was not linear and hepcidin was very low in severe malarial anemia. Parasite density, IL-10 and IL-6 were significantly associated with hepcidin concentration. Hepcidin response to acute malaria supports the notion of iron sequestration during acute malaria infection and suggests that iron administration during acute malaria is futile. These data suggest iron supplementation policies should take into account the high hepcidin levels and probable poor utilization of iron for up to one week after treatment for the majority of patients with acute malaria.

Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania.

BACKGROUND: The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam. METHODS AND FINDINGS: A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8-11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8-8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0-2.9); p = 0.044] as determined by logistic regression. CONCLUSIONS: Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.