A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

Kidney Function Decline among Black Patients with Sickle Cell Trait and Sickle Cell Disease: An Observational Cohort Study.

BACKGROUND: Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. METHODS: Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. RESULTS: We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. CONCLUSIONS: Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.

How I treat anemia in pregnancy: iron, cobalamin, and folate.

Anemia of pregnancy, an important risk factor for fetal and maternal morbidity, is considered a global health problem, affecting almost 50% of pregnant women. In this article, diagnosis and management of iron, cobalamin, and folate deficiencies, the most frequent causes of anemia in pregnancy, are discussed. Three clinical cases are considered. Iron deficiency is the most common cause. Laboratory tests defining iron deficiency, the recognition of developmental delays and cognitive abnormalities in iron-deficient neonates, and literature addressing the efficacy and safety of IV iron in pregnancy are reviewed. An algorithm is proposed to help clinicians diagnose and treat iron deficiency, recommending oral iron in the first trimester and IV iron later. Association of folate deficiency with neural tube defects and impact of fortification programs are discussed. With increased obesity and bariatric surgery rates, prevalence of cobalamin deficiency in pregnancy is rising. Low maternal cobalamin may be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity. The importance of treating cobalamin deficiency in pregnancy is considered. A case of malarial anemia emphasizes the complex relationship between iron deficiency, iron treatment, and malaria infection in endemic areas; the heightened impact of combined etiologies on anemia severity is highlighted.

Cardiovascular Outcomes in African Americans with Sickle Cell Trait and Chronic Kidney Disease.

BACKGROUND: Sickle cell trait (SCT) is common among African Americans and has been historically considered to be benign. Recently, SCT has been associated with an increased risk for chronic kidney disease (CKD) and cardiovascular disease in the general population. Our understanding of SCT has been extrapolated largely from data of patients with sickle cell disease (SCD). Notably, in SCD, the outcomes differ by sex. The effect of SCT on cardiovascular risk in the African American CKD population is unknown, and the interaction between SCT and sex on cardiovascular risk has not been investigated. METHODS: We performed a 2-center retrospective cohort study of all African American patients with SCT using international classification of disease diagnosis codes and CKD (using the 2012 Kidney Disease Improving Global Outcomes criteria) with at least 1 year of follow-up between January 2005 and December 2017. A reference group of -African American CKD patients without SCT was used as a comparator during the same period. SCT patients and the reference patients were matched at baseline for age, sex, comorbidities, and proteinuria. Primary outcomes were incident coronary artery disease (CAD), incident stroke, and all-cause mortality. Analysis of effect modification between sex and SCT on primary outcomes was performed. RESULTS: We identified 621 African American CKD patients, 217 SCT patients, and 404 reference patients. The mean age was 56 ± 13 years and 66% were female. The mean estimated glomerular filtration rate was 69 ± 30 mL/min. The mean follow-up time was 8 ± 4 years. There were no significant differences in the primary outcomes comparing SCT patients to matched controls. The interaction term between SCT and sex, however, was significant in the CAD model (p < 0.01). Stratification by sex showed no increased risk in females but a significantly increased risk for CAD in male SCT patients (hazard ratio [HR] 2.14; 95% CI 1.18-3.86), which persisted after multivariable analysis (HR 2.13; 95% CI 1.17-3.86). CONCLUSION: SCT is associated with an increased risk for CAD in African American males with CKD. The excess risk in males with SCT appears to follow the same pattern as risk in males with SCD. Larger studies are needed to confirm these findings.

A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.

Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON-IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open-label, comparative, multi-center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co-primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co-primary safety objective was met, and no risk difference was observed between groups. The co-primary efficacy endpoint of non-inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.

Sickle Cell Nephropathy in the Pediatric Population.

BACKGROUND: Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. SUMMARY: SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large-scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit.

A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is common in many chronic diseases, and intravenous (IV) iron offers a rapid and efficient iron correction. This trial compared the efficacy and safety of iron isomaltoside (also known as ferric derisomaltose) and iron sucrose in patients with IDA who were intolerant of, or unresponsive to, oral iron. The trial was an open­label, comparative, multi­center trial. Five hundred and eleven patients with IDA from different causes were randomized 2:1 to iron isomaltoside or iron sucrose and followed for 5 weeks. The cumulative dose of iron isomaltoside was based on body weight and hemoglobin (Hb), administered as either a 1000 mg infusion over more than 15 minutes or 500 mg injection over 2 minutes. The cumulative dose of iron sucrose was calculated according to Ganzoni and administered as repeated 200 mg infusions over 30 minutes. The mean cumulative dose of iron isomaltoside was 1640.2 (standard deviation (SD): 357.6) mg and of iron sucrose 1127.9 (SD: 343.3) mg. The primary endpoint was the proportion of patients with a Hb increase ≥2 g/dL from baseline at any time between weeks 1­5. Both non­inferiority and superiority were confirmed for the primary endpoint, and a shorter time to Hb increase ≥2 g/dL was observed with iron isomaltoside. For all biochemical efficacy parameters, faster and/or greater improvements were found with iron isomaltoside. Both treatments were well tolerated; 0.6% experienced a serious adverse drug reaction. Iron isomaltoside was more effective than iron sucrose in achieving a rapid improvement in Hb. Furthermore, iron isomaltoside has an advantage over iron sucrose in allowing higher cumulative dosing in fewer administrations. Both treatments were well tolerated in a broad population with IDA.

A systematic literature review and meta-analysis of the incidence of serious or severe hypersensitivity reactions after administration of ferric derisomaltose or ferric carboxymaltose.

BACKGROUND: Intravenous iron is the preferred treatment for patients with iron deficiency anemia in a variety of clinical situations. Although uncommon, administration of modern IV iron formulations can result in hypersensitivity reactions (HSRs) and, rarely, anaphylactic or anaphylactoid reactions. AIM: The objective of the present study was to systematically review the literature to identify and analyze data on the incidence of HSRs after administration of ferric derisomaltose (FDI) or ferric carboxymaltose (FCM). METHOD: A prospectively-registered systematic literature review was conducted to identify prospective randomized controlled trials comparing FDI and FCM with other intravenous iron formulations or oral iron. Searches were conducted in PubMed (including MEDLINE), EMBASE, and the Cochrane Library in November 2020. The relative incidence of serious or severe HSRs occurring on the day or day after dosing of intravenous iron, recorded under the standardized Medical Dictionary for Regulatory Activities query for anaphylactic reaction. RESULTS: Data were obtained from seven randomized controlled trials of FCM (N = 2683) and ten of FDI (N = 3474) enrolling 10,467 patients in total. The number of patients experiencing any serious or severe HSR event was 29/2683 (1.08%) with FCM versus 5/3474 with FDI (0.14%). Bayesian inference of proportions showed the event rates to be significantly lower with FDI relative to FCM. CONCLUSION: HSR events were uncommon with both intravenous iron formulations; however, the present study showed a significantly lower incidence of HSRs with FDI relative to FCM. Further large-scale, head-to-head trials of the iron formulations would be required to confirm this finding.

Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery.

PURPOSE: Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. MATERIALS AND METHODS: Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. RESULTS: The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. CONCLUSIONS: In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated.

Epidemiology and Predictors of all-cause 30-Day readmission in patients with sickle cell crisis.

The 30-day readmission rate after hospitalization for a sickle cell crisis (SCC) is extremely high. Accurate information on readmission diagnoses, total readmission costs and factors associated with readmission is required to effectively plan resource allocation and to plan interventions to reduce readmission rates. The present study aimed to examine readmission diagnoses and factors associated with all-cause 30-day readmission after hospitalization for SCC. We analyzed 2016 nationwide readmission database (NRD) to identify patterns of 30-day readmission by patient demographic characteristics and time after hospitalization for SCC. We estimated the percentage and most common readmission diagnoses for 30-day and 7-day readmissions after discharge. We studied the relationship between risk factors and readmission and the impact of readmission on patient outcomes and resulting financial burden on health care in dollars. In 2016, of 67,887 discharges after index hospitalizations, 18099 (26.9%) were readmitted within 30-days. Of all readmissions, 5166 (7.6%) were readmitted within 7 days. The spectrum of readmission diagnoses was largely similar in both 30-day and 7-day readmission with more than 80% patients in both time periods readmitted with diagnoses related to SCC. The mean length of stay for readmitted patients was significantly longer than the index hospitalization (5.3 days (5.1-5.5) vs 4.9 days (CI 4.8-5.1, p < 0.01). Also, the mean cost of hospitalization in readmitted patients $8485 was significantly higher than the index hospitalization $8064 p < 0.01. In 2016, readmission among patients with SCC incurred an additional 95,445 hospitalization days resulting a total charge of $609 million and a total cost of $152 million in the US. On Multivariate analysis, age group 18-30 years, discharge against medical advice, higher Charlson comorbidity index, low socioeconomic status and admission at high volume centers were associated with a higher likelihood of 30-day readmission. Among patients hospitalized for SCC, 30-day readmissions were frequent throughout the month post hospitalization and resulted in an enormous financial burden on the United States healthcare system.