Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

Effect of Donor Sex on Recipient Mortality in Transfusion.

BACKGROUND: Conflicting observational evidence exists regarding the association between the sex of red-cell donors and mortality among transfusion recipients. Evidence to inform transfusion practice and policy is limited. METHODS: In this multicenter, double-blind trial, we randomly assigned patients undergoing red-cell transfusion to receive units of red cells from either male donors or female donors. Patients maintained their trial-group assignment throughout the trial period, including during subsequent inpatient and outpatient encounters. Randomization was conducted in a 60:40 ratio (male donor group to female donor group) to match the historical allocation of red-cell units from the blood supplier. The primary outcome was survival, with the male donor group as the reference group. RESULTS: A total of 8719 patients underwent randomization before undergoing transfusion; 5190 patients were assigned to the male donor group, and 3529 to the female donor group. At baseline, the mean (±SD) age of the enrolled patients was 66.8±16.4 years. The setting of the first transfusion was as an inpatient in 6969 patients (79.9%), of whom 2942 (42.2%) had been admitted under a surgical service. The baseline hemoglobin level before transfusion was 79.5±19.7 g per liter, and patients received a mean of 5.4±10.5 units of red cells in the female donor group and 5.1±8.9 units in the male donor group (difference, 0.3 units; 95% confidence interval [CI], -0.1 to 0.7). Over the duration of the trial, 1141 patients in the female donor group and 1712 patients in the male donor group died. In the primary analysis of overall survival, the adjusted hazard ratio for death was 0.98 (95% CI, 0.91 to 1.06). CONCLUSIONS: This trial showed no significant difference in survival between a transfusion strategy involving red-cell units from female donors and a strategy involving red-cell units from male donors. (Funded by the Canadian Institutes of Health Research; iTADS ClinicalTrials.gov number, NCT03344887.).

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Tranexamic Acid to Prevent Obstetrical Hemorrhage after Cesarean Delivery.

BACKGROUND: Prophylactic use of tranexamic acid at the time of cesarean delivery has been shown to decrease the calculated blood loss, but the effect on the need for blood transfusions is unclear. METHODS: We randomly assigned patients undergoing cesarean delivery at 31 U.S. hospitals to receive either tranexamic acid or placebo after umbilical-cord clamping. The primary outcome was a composite of maternal death or blood transfusion by hospital discharge or 7 days post partum, whichever came first. Key secondary outcomes were estimated intraoperative blood loss of more than 1 liter (prespecified as a major secondary outcome), interventions for bleeding and related complications, the preoperative-to-postoperative change in the hemoglobin level, and postpartum infectious complications. Adverse events were assessed. RESULTS: A total of 11,000 participants underwent randomization (5529 to the tranexamic acid group and 5471 to the placebo group); scheduled cesarean delivery accounted for 50.1% and 49.2% of the deliveries in the respective groups. A primary-outcome event occurred in 201 of 5525 participants (3.6%) in the tranexamic acid group and in 233 of 5470 (4.3%) in the placebo group (adjusted relative risk, 0.89; 95.26% confidence interval [CI], 0.74 to 1.07; P = 0.19). Estimated intraoperative blood loss of more than 1 liter occurred in 7.3% of the participants in the tranexamic acid group and in 8.0% of those in the placebo group (relative risk, 0.91; 95% CI, 0.79 to 1.05). Interventions for bleeding complications occurred in 16.1% of the participants in the tranexamic acid group and in 18.0% of those in the placebo group (relative risk, 0.90; 95% CI, 0.82 to 0.97); the change in the hemoglobin level was -1.8 g per deciliter and -1.9 g per deciliter, respectively (mean difference, -0.1 g per deciliter; 95% CI, -0.2 to -0.1); and postpartum infectious complications occurred in 3.2% and 2.5% of the participants, respectively (relative risk, 1.28; 95% CI, 1.02 to 1.61). The frequencies of thromboembolic events and other adverse events were similar in the two groups. CONCLUSIONS: Prophylactic use of tranexamic acid during cesarean delivery did not lead to a significantly lower risk of a composite outcome of maternal death or blood transfusion than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT03364491.).

Effectiveness of ferritin-guided donation intervals in whole-blood donors in the Netherlands (FIND'EM): a stepped-wedge cluster-randomised trial.

BACKGROUND: Whole-blood donors are at increased risk for iron deficiency and anaemia. The current standard of haemoglobin monitoring is insufficient to ensure the maintenance of proper iron reserves and donor health. We aimed to determine the effects of ferritin-guided donation intervals for blood donor health and blood supply in the Netherlands. METHODS: In this stepped-wedge cluster-randomised trial (FIND'EM), the 138 fixed and mobile donation centres in the Netherlands are organised into 29 geographical clusters and the clusters were randomly assigned to four treatment groups, with two groups being further split into two per a protocol amendment. Eligible donors were whole-blood donors who consented for use of their leftover material in the study. Each group was sequentially crossed over from the existing policy (haemoglobin-based screening; control) to a ferritin-guided donation interval policy over a 3-year period. In the intervention groups, in addition to the existing haemoglobin screening, ferritin was measured in all new donors and at every fifth donation in repeat donors. Subsequent donation intervals were extended to 6 months if ferritin concentrations were 15-30 ng/mL and to 12 months if they were less than 15 ng/mL. Outcomes were measured cross-sectionally across all donation centres at four timepoints. Primary outcomes were ferritin and haemoglobin concentrations, iron deficiency, and haemoglobin-based deferrals. We assessed all outcomes by sex and menopausal status and significance for primary outcomes was indicated by a p value of less than 0·0125. This trial is registered in the Dutch trial registry, NTR6738, and is complete. FINDINGS: Between Sept 11, 2017, and Nov 27, 2020, 412 888 whole-blood donors visited a donation centre, and we did measurements on samples from 37 621 donations from 36 099 donors. Over 38 months, ferritin-guided donation intervals increased mean ferritin concentrations (by 0·18 log10 ng/mL [95% CI 0·15-0·22; p<0·0001] in male donors, 0·10 log10 ng/mL [0·06-0·15; p<0·0001] in premenopausal female donors, and 0·17 log10 ng/mL [0·12-0·21; p<0·0001] in postmenopausal female donors) and mean haemoglobin concentrations (by 0·30 g/dL [95% CI 0·22-0·38; p<0·0001] in male donors, 0·12 g/dL [0·03-0·20; p<0·0074] in premenopausal female donors, and 0·16 g/dL [0·05-0·27; p<0·0044] in postmenopausal female donors). Iron deficiency decreased by 36-38 months (odds ratio [OR] 0·24 [95% CI 0·18-0·31; p<0·0001] for male donors, 0·49 [0·37-0·64; p<0·0001] for premenopausal female donors, and 0·24 [0·15-0·37; p<0·0001] for postmenopausal female donors). At 36-38 months, haemoglobin-based deferral decreased significantly in male donors (OR at 36-38 months 0·21 [95% CI 0·10-0·40, p<0·0001]) but not significantly in premenopausal or postmenopausal female donors (0·81 [0·54-1·20; p=0·29] and 0·50 [95% CI 0·25-0·98; p=0·051], respectively). INTERPRETATION: Ferritin-guided donation intervals significantly improved haemoglobin and ferritin concentrations and significantly decreased iron deficiency over the study period. Haemoglobin-based deferrals decreased significantly for male donors, but not female donors. Although this intervention is overall beneficial for maintenance of iron and haemoglobin concentrations in donors, increased efforts are needed to recruit and retain donors. FUNDING: The Sanquin Research Programming Committee.

Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified ß-globin gene, which produces an antisickling hemoglobin, HbAT87Q. METHODS: In this ongoing phase 1-2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of four severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least four vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up. RESULTS: As of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAT87Q contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells. Hemolysis markers were reduced. Among the 25 patients who could be evaluated, all had resolution of severe vaso-occlusive events, as compared with a median of 3.5 events per year (range, 2.0 to 13.5) in the 24 months before enrollment. Three patients had a nonserious adverse event related or possibly related to LentiGlobin that resolved within 1 week after onset. No cases of hematologic cancer were observed during up to 37.6 months of follow-up. CONCLUSIONS: One-time treatment with LentiGlobin resulted in sustained production of HbAT87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events. (Funded by Bluebird Bio; HGB-206 ClinicalTrials.gov number, NCT02140554.).

Betibeglogene Autotemcel Gene Therapy for Non-ß0/ß0 Genotype ß-Thalassemia.

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent ß-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the ß-globin (ßA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent ß-thalassemia and a non-ß0/ß0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-ß0/ß0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).

Mitapivat versus Placebo for Pyruvate Kinase Deficiency.

BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency. METHODS: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures. RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo. CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).

How I treat anemia with red blood cell transfusion and iron.

Severe anemia is commonly treated with red blood cell transfusion. Clinical trials have demonstrated that a restrictive transfusion strategy of 7 to 8 g/dL is as safe as a liberal transfusion strategy of 9 to 10 g/dL in many clinical settings. Evidence is lacking for subgroups of patients, including those with preexisting coronary artery disease, acute myocardial infarction, congestive heart failure, and myelodysplastic neoplasms. We present 3 clinical vignettes that highlight the clinical challenges in caring for patients with coronary artery disease with gastrointestinal bleeding, congestive heart failure, or myelodysplastic neoplasms. We emphasize that transfusion practice should be guided by patient symptoms and preferences in conjunction with the patient's hemoglobin concentration. Along with the transfusion decision, evaluation and management of the etiology of the anemia is essential. Iron-restricted erythropoiesis is a common cause of anemia severe enough to be considered for red blood cell transfusion but diagnosis and management of absolute iron deficiency anemia, the anemia of inflammation with functional iron deficiency, or their combination may be problematic. Intravenous iron therapy is generally the treatment of choice for absolute iron deficiency in patients with complex medical disorders, with or without coexisting functional iron deficiency.

Nocturnal hypoxaemia is common in adults with sickle cell anaemia.

The symptoms and sequelae of sickle cell anaemia (SCA) are caused by the polymerization of deoxygenated sickle haemoglobin, and people with SCA may be uniquely susceptible to adverse outcomes from hypoxia and haemoglobin desaturation. We examined by oximetry adults (aged 18-45 years) with SCA presenting symptoms indicative of polysomnography, at a single institution, irrespective of treatment, for nocturnal hypoxaemia. Clinical labs and blood for in vitro assessments were taken upon enrolment and after 8-12 weeks of oxygen therapy or observation. Of 21 screened participants, nine (43%) had sufficient nocturnal hypoxaemia to warrant oxygen therapy (≥5 min at SpO2 ≤ 88%). Time spent at SpO2 ≤ 88% associated with age (p = 0.0092), annual hospitalizations (p = 0.0018) and anaemia (p = 0.0139), as well as plasma levels of TNFα (p = 0.0019) and IL-4 (p = 0.0147). Longitudinal analysis showed that WBC significantly decreased during the follow-up period in hypoxic individuals but not in non-hypoxic individuals (p = 0.0361 and p = 0.6969 respectively). Plasma levels of CCL2 and IL-1ra tended to increase, while levels of red blood cell reactive oxygen species tended to decrease with oxygen therapy. Overall, nocturnal hypoxaemia was common in this pilot study population and associated with plausible clinical comorbidities; oxygen therapy may decrease inflammation and oxidative damage in hypoxic individuals.

Determinants of the haemoglobin level in patients with sickle cell disease living in sub-Saharan Africa: Major impact of the country of residence and independent effects of leucocyte and platelet counts and haemolysis.

The degree of anaemia in sickle cell disease (SCD) is a well-known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio-demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sß0, 587 SC and 176 Sß + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sß0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sß + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region.

Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.

BACKGROUND: Universal provision of iron supplements (drops or syrup) or multiple micronutrient powders to young children in low-to-middle-income countries where anemia is prevalent is recommended by the World Health Organization and widely implemented. The functional benefits and safety of these interventions are unclear. METHODS: We conducted a three-group, double-blind, double-dummy, individually randomized, placebo-controlled trial to assess the immediate and medium-term benefits and risks of 3 months of daily supplementation with iron syrup or iron-containing multiple micronutrient powders, as compared with placebo, in 8-month-old children in rural Bangladesh. The primary outcome was cognitive development, as assessed by the cognitive composite score on the Bayley Scales of Infant and Toddler Development, third edition, immediately after completion of the assigned 3-month regimen; scores range from 55 to 145, with higher scores indicating better cognitive performance. Secondary outcomes included the cognitive composite score at 9 months after completion of the assigned regimen; behavioral, language, and motor development, as well as growth and hematologic markers, immediately after completion and at 9 months after completion; and safety. RESULTS: We randomly assigned 3300 infants to receive iron syrup (1101 infants), multiple micronutrient powders (1099), or placebo (1100) daily. After completion of the assigned 3-month regimen, no apparent effect on the cognitive composite score was observed with iron syrup as compared with placebo (mean between-group difference in change in score from baseline, -0.30 points; 95% confidence interval [CI], -1.08 to 0.48) or with multiple micronutrient powders as compared with placebo (mean between-group difference in change in score from baseline, 0.23 points; 95% CI, -0.55 to 1.00). No apparent effect on any other developmental or growth outcome was observed immediately after completion of the assigned regimen or at 9 months after completion. At 9 months after completion of the assigned regimen, the prevalences of anemia, iron deficiency, and iron deficiency anemia increased in all three trial groups but remained lower among the children who received iron syrup or multiple micronutrient powders than among those who received placebo. The risk of serious adverse events and incidence of symptoms of infection were similar in the three trial groups. CONCLUSIONS: In this trial involving infants in Bangladesh, 3 months of daily supplementation with iron syrup or multiple micronutrient powders did not appear to have an effect on child development or other functional outcomes as compared with placebo. (Funded by the National Health and Medical Research Council of Australia; BRISC Australian New Zealand Clinical Trials Registry number, ACTRN12617000660381.).

Sutimlimab in Cold Agglutinin Disease.

BACKGROUND: Cold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway. METHODS: We conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol. RESULTS: A total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred. CONCLUSIONS: In patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Daprodustat for the Treatment of Anemia in Patients Undergoing Dialysis.

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

Daprodustat for the Treatment of Anemia in Patients Not Undergoing Dialysis.

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

The Diagnostic Performance of Fecal Immunochemical Tests for Detecting Advanced Neoplasia at Surveillance Colonoscopy.

BACKGROUND & AIMS: An increasing burden on health care resources has resulted in a backlog of individuals requiring colonoscopy, with delays in surveillance possibly detrimental for individuals at increased risk of colorectal cancer (CRC). This study investigated the use of a 2-sample fecal immunochemical test (FIT) to establish those most likely to have advanced neoplasia (AN) and in need of prioritized surveillance colonoscopy. METHODS: This was a prospective study conducted in the tertiary care setting. Participants completed a 2-sample FIT (OC-Sensor, Eiken Chemical Company) within 90 days of surveillance colonoscopy. The sensitivity of FIT for detection of AN (CRC or advanced adenoma) in moderate- and high-risk individuals was determined at fecal hemoglobin thresholds between 2 and 80 µg/g feces. RESULTS: A total of 766 patients were included (median age, 66.1 years [interquartile range, 58.1-72.9]; 49.9% male), with AN detected in 8.6% (66/766, including 5 CRC). For moderate-risk individuals (with prior history of adenoma or a significant family history of CRC), sensitivity of FIT for AN ranged from 73.5% at 2 µg/g feces, to 10.2% at 80 µg/g feces. For high-risk conditions (confirmed/suspected genetic syndromes or prior CRC), sensitivity of FIT was similar, ranging from 70.6% at the lowest positivity threshold of 2 µg/g feces, to 11.8% at 80 µg/g feces. Independent variables in the whole cohort for association with detection of AN at surveillance colonoscopy were age (odds ratio, 1.03; 95% confidence interval, 1.00-1.06) and FIT hemoglobin result ≥10 µg/g feces (odds ratio, 1.81; 95% confidence interval, 1.04-3.16). CONCLUSIONS: The use of FIT before surveillance colonoscopy provides clinicians with insights into the risk of AN. This raises the possibility of a method to triage individuals, facilitating the more efficient management of endoscopic resources.

Non-arterial line cardiac output calculation misclassifies exercise pulmonary hypertension and increases risk of data loss particularly in black, scleroderma and Raynaud's patients during invasive exercise testing.

BACKGROUND: The direct Fick principle is the standard for calculating cardiac output (CO) to detect CO-dependent conditions like exercise pulmonary hypertension (ePH). Fick COarterial incorporates arterial haemoglobin (Hba) and oxygen saturation (S aO2 ) with oxygen consumption from exercise testing, while Fick COnon-arterial substitutes mixed venous haemoglobin (Hbmv) and peripheral oxygen saturation (S pO2 ) in the absence of an arterial line. The decision to employ an arterial catheter for exercise testing varies, and discrepancies in oxygen saturation and haemoglobin between arterial and non-arterial methods may lead to differences in Fick CO, potentially affecting ePH classification. METHODS: We performed a retrospective analysis of 296 consecutive invasive cardiopulmonary exercise testing (iCPET) studies comparing oxygen saturation from pulse oximetry (S pO2 ) and radial arterial (S aO2 ), Hba and Hbmv, and CO calculated with arterial (COarterial) and non-arterial (COnon-arterial) values. We assessed the risk of misclassification of pre- and post-capillary ePH and data loss due to inaccurate S pO2 . RESULTS: When considering all stages from rest to peak exercise, Hba and Hbmv demonstrated high correlation, while S pO2 and S aO2 as well as COarterial and COnon-arterial demonstrated low correlation. Data loss was significantly higher across all stages of exercise for S pO2 (n=346/1926 (18%)) compared to S aO2 (n=17/1923 (0.88%)). We found that pre- and post-capillary ePH were misclassified as COnon-arterial data (n=7/41 (17.1%) and n=2/23 (8.7%), respectively). Patients with scleroderma and/or Raynaud's (n=11/33 (33.3%)) and black patients (n=6/19 (31.6%)) had more S pO2 data loss. CONCLUSION: Reliance upon S pO2 during invasive exercise testing results in the misclassification of pre- and post-capillary ePH, and unmeasurable S pO2 for black, scleroderma and Raynaud's patients can preclude accurate exercise calculations, thus limiting the diagnostic and prognostic value of invasive exercise testing without an arterial line.