Abstract

INTRODUCTION Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. METHODS This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. DISCUSSION/CONCLUSION Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.

Abstract

OBJECTIVE To evaluate the clinical effect of high-dose intravenous immunoglobulin (HDIVIG) single dose and pulse therapy combined with small-dose prednisone acetate in the treatment of patients with Kawasaki disease (KD). METHODS Eighty patients with KD from Baoding Children's Hospital, China, were randomly divided into two groups: the experimental group and the control group, each with 40 cases. Patients in the experimental group were treated with HDIVIG single dose, pulse therapy combined with low-dose prednisone acetate, while patients in the control group were treated with conventional-dose immunoglobulin. Patients in both groups were treated with aspirin orally, and given symptomatic treatment including anti-inflammatory, nutritional support, correction of water and electrolyte disturbance and acid-base balance. Peripheral venous blood samples were drawn from all patients at the time of admission, Day-1, Day-7 and Day-14 after treatment, and in the basic state of getting up in the morning, and then the levels of tumor necrosis factor (TNF-a), C-reactive protein (CRP), interleukin-6 (IL-6) and other inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The time of body temperature falling to normal, lymph node swelling recovery, hands and feet swelling, mucosal hyperemia regression after treatment in the two groups was recorded, and the treatment effect of the two groups was comprehensively evaluated. RESULTS After treatment, the levels of inflammatory factors such as TNF-a, CRP, IL-6 in the experimental group were significantly lower than those in the control group, with a statistically significant difference (P<0.05). In addition, the time of body temperature falling to normal, lymph node swelling recovery, hands and feet swelling, and mucosal hyperemia regression in the experimental group was significantly shorter than that in the control group (p=0.00). The effective rate of the experimental group was 95% and that of the control group was 80%, with a statistically significant difference (p=0.04). CONCLUSION HDIVIG single dose, pulse therapy combined with small-dose prednisone acetate has a favourable therapeutic effect in the treatment of patients with KD, by which the inflammatory factors can be significantly improved, clinical symptoms and weight can be quickly ameliorated, and therapeutic effect can be enhanced.

Abstract

IMPORTANCE The optimal transfusion strategy in patients with acute myocardial infarction and anemia is unclear. OBJECTIVE To determine whether a restrictive transfusion strategy would be clinically noninferior to a liberal strategy. DESIGN, SETTING, AND PARTICIPANTS Open-label, noninferiority, randomized trial conducted in 35 hospitals in France and Spain including 668 patients with myocardial infarction and hemoglobin level between 7 and 10 g/dL. Enrollment could be considered at any time during the index admission for myocardial infarction. The first participant was enrolled in March 2016 and the last was enrolled in September 2019. The final 30-day follow-up was accrued in November 2019. INTERVENTIONS Patients were randomly assigned to undergo a restrictive (transfusion triggered by hemoglobin ≤8; n = 342) or a liberal (transfusion triggered by hemoglobin ≤10 g/dL; n = 324) transfusion strategy. MAIN OUTCOMES AND MEASURES The primary clinical outcome was major adverse cardiovascular events (MACE; composite of all-cause death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia) at 30 days. Noninferiority required that the upper bound of the 1-sided 97.5% CI for the relative risk of the primary outcome be less than 1.25. The secondary outcomes included the individual components of the primary outcome. RESULTS Among 668 patients who were randomized, 666 patients (median [interquartile range] age, 77 [69-84] years; 281 [42.2%] women) completed the 30-day follow-up, including 342 in the restrictive transfusion group (122 [35.7%] received transfusion; 342 total units of packed red blood cells transfused) and 324 in the liberal transfusion group (323 [99.7%] received transfusion; 758 total units transfused). At 30 days, MACE occurred in 36 patients (11.0% [95% CI, 7.5%-14.6%]) in the restrictive group and in 45 patients (14.0% [95% CI, 10.0%-17.9%]) in the liberal group (difference, -3.0% [95% CI, -8.4% to 2.4%]). The relative risk of the primary outcome was 0.79 (1-sided 97.5% CI, 0.00-1.19), meeting the prespecified noninferiority criterion. In the restrictive vs liberal group, all-cause death occurred in 5.6% vs 7.7% of patients, recurrent myocardial infarction occurred in 2.1% vs 3.1%, emergency revascularization prompted by ischemia occurred in 1.5% vs 1.9%, and nonfatal ischemic stroke occurred in 0.6% of patients in both groups. CONCLUSIONS AND RELEVANCE Among patients with acute myocardial infarction and anemia, a restrictive compared with a liberal transfusion strategy resulted in a noninferior rate of MACE after 30 days. However, the CI included what may be a clinically important harm. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02648113.

Abstract

BACKGROUND Studies evaluating the role of both corticosteroids and platelet-rich plasma (PRP) in the treatment of rotator cuff (RC) tendinopathies have been contradicting. We compared structural and clinical changes in RC muscles after corticosteroids and PRP injections. METHODS This is a randomized double-blind clinical trial. All individuals with diagnosis of RC tendinitis during 2014-2017 were considered. Individuals were randomly allocated to either receive PRP or corticosteroids. Overall, 3cc of PRP was injected within the subacromial joint and another 3cc was injected at the site of the tendon tear, under the guide of sonography. For the corticosteroid group, 1cc of Depo-medrol 40mg and 1cc of lidocaine (2%) was injected within the subacromial joint. RESULTS Overall, 58 patients entered the study. Comparison of pain, range of motion (ROM), Western Ontario RC (WORC), Disability of Arm-Hand-Shoulder (DASH) scores, and supraspinatus thickness showed significant improvement during follow-ups in both groups (p<0.05). During 3 months of follow-up, pain improvement was significantly better within the PRP group during (from 6.66±2.26 to 3.08±2.14 and 5.53±1.80 to 3.88±1.99, respectively; p=0.023). Regarding ROM, the PRP group had significant improvement in adduction (20.50°±8.23° to 28°±3.61° and 23.21°±7.09° to 28.46°±4.18° for the PRP and corticosteroid groups, respectively; p=0.011) and external rotation (59.66°±23.81° to 76.66°±18.30° and 57.14°±24.69° to 65.57°±26.39°, for the PRP and corticosteroid groups, respectively; p=0.036) compared to the corticosteroid group. CONCLUSION We found that PRP renders similar results to that of corticosteroids in most clinical aspects among patients with RC tendinopathies; however, pain and ROM may show more significant improvement with the use of PRP. Considering that the use of corticosteroids may be contraindicated in some patients and may be associated with the risk of tendon rupture, we suggest the use of PRP in place of corticosteroid-based injections among patients with RC tendinopathy. TRIAL REGISTRATION Clinical trial registration code: IRCT201302174251N9.

Abstract

BACKGROUND Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). METHODS This randomised, open-label, active-controlled phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin within 10.0-12.0 g/dL. The primary endpoint was haemoglobin response in the full analysis set (FAS), defined as haemoglobin ≥11.0 g/dL and haemoglobin change from baseline (CFB) ≥1.0 g/dL in patients with baseline haemoglobin >8.0 g/dL or CFB ≥2.0 g/dL in patients with baseline haemoglobin ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (noninferiority margin, -15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous iron use, change in mean arterial pressure (MAP), and time to hypertension occurrence. Adverse events were assessed. RESULTS Of 616 randomised patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Haemoglobin response with roxadustat was noninferior to DA (roxadustat: 256/286, 89.5% vs. DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval, 5.66-17.36%). Roxadustat maintained haemoglobin for up to 2 years. Roxadustat was noninferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first intravenous iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACE) and MACE + (MACE: 0.81 [0.52, 1.25], P = 0.339; MACE+: 0.90 [0.61, 1.32], P = 0.583). CONCLUSION Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining haemoglobin levels for up to 104 weeks.

Abstract

Despite encouraging results reported with regards to Platelet-rich plasma (PRP) application in osteoarthritis (OA) knee, still critical issues like conclusive structural evidence of its efficacy, standard dose and good manual method of preparation to obtain high yield remains unanswered. Present study is an attempt to optimise the dose and concentration of therapeutic PRP and its correlation with structural, physiologic efficacy with a new manual method of PRP preparation. A total of one hundred and fifty patients were randomized to receive either PRP (10 billion platelets) or hyaluronic acid (HA; 4 ml; 75 patients in each group) and followed up till 1 year. An addition of filtration step with 1 µm filter in manual PRP processing improved platelet recovery upto 90%. Significant improvements in WOMAC (51.94 ± 7.35 vs. 57.33 ± 8.92; P < 0.001), IKDC scores (62.8 ± 6.24 vs 52.7 ± 6.39; P < 0.001), 6-min pain free walking distance (+ 120 vs. + 4; P < 0.001) persisted in PRP compared to HA group at 1 year. Significant decline IL-6 and TNF-α levels observed in PRP group (P < 0.05) compared to HA at 1 month. Study demonstrated that an absolute count of 10 billion platelets is crucial in a PRP formulation to have long sustained chondroprotective effect upto one year in moderate knee OA.

Abstract

INTRODUCTION Patients with end-stage kidney disease (ESKD) suffer from functional iron deficiency where despite the presence of sufficient iron stores in the body, adequate iron is unavailable for heme synthesis. This study hypothesis was that in patients undergoing hemodialysis (HD), administration of intravenous (IV) ascorbic acid (AA) exerts a good effect on the management of anemia, either by increasing the mobilization of iron from tissue stores or acting as an antioxidant to overcome the inflammatory block and increase the erythropoietin sensitivity. METHODS Fifty patients with ESRD who were on regular HD were included in the study. Patients' ferritin levels ranged from 500 to 1200 ng/mL with transferrin saturation of 30% or more. However, all patients were anemic and received erythropoietin therapy. Iron therapy was discontinued in the first group, whereas it was continued in the second group that received IV AA. RESULTS A significant increase in the levels of Hb was observed in the second group after 6 months despite the decrease in ferritin levels in both the groups. Transferrin saturation decreased in both groups, the decrease being more in the first group. The levels of C-reactive protein (CRP) decreased in the second group, whereas these increased in the first group. CONCLUSIONS Intravenous AA as an adjuvant therapy with iron exerts a favorable and significant effect on the Hb, serum ferritin, and CRP levels in patients with ESKD having anemia. The discontinuation of iron therapy only decreases the serum ferritin levels and does not improve the Hb or CRP levels.

Abstract

BACKGROUND Pressure ulcer is one of the common complications occurring in spinal cord injury (SCI) patients. Platelet-rich plasma (PRP) has been found useful in the treatment of pressure ulcers in few studies. The purpose of this study was to evaluate the role of PRP in pressure ulcer healing in comparison to hydrogel dressing in SCI patients. METHODS In this randomized interventional study, 52 patients of SCI having pressure ulcers of grade III/IV were randomized into two groups of 26 each. In group A patients, hydrogel dressing was done while freshly prepared PRP was used in patients of group B. Pressure ulcers were evaluated at baseline and after three weeks and six weeks in terms of ulcer surface area, volume, Pressure Ulcer Scale for Healing (PUSH) score, histopathology, and ulcer healing parameters. Data were collected and quantitative variables were compared using unpaired t-test or Mann-Whitney test between the two groups and qualitative variables were compared using the chi-square test or Fisher's exact test. A p-value of <0.05 was considered statistically significant. RESULTS Baseline characteristics were comparable in both groups. There was a significant improvement in ulcers in terms of surface area, volume, and PUSH score in both the groups but it was comparable (p-value >0.05). There was a significant improvement in the PRP group as compared to the other group in terms of epithelization, granulation, and neovascularization at three and six-week follow-up. CONCLUSIONS This study suggests that PRP is a possible and better alternative to conventional dressing methods for the treatment of pressure ulcers.

Abstract

BACKGROUND Erythrocyte transfusions are independently associated with acute kidney injury. Kidney injury may be consequent to the progressive hematologic changes that develop during storage. This study therefore tested the hypothesis that prolonged erythrocyte storage increases posttransfusion acute kidney injury. METHODS The Informing Fresh versus Old Red Cell Management (INFORM) trial randomized 31,497 patients to receive either the freshest or oldest available matching erythrocyte units and showed comparable mortality with both. This a priori substudy compared the incidence of posttransfusion acute kidney injury in the randomized groups. Acute kidney injury was defined by the creatinine component of the Kidney Disease: Improving Global Outcomes criteria. RESULTS The 14,461 patients included in this substudy received 40,077 erythrocyte units. For patients who received more than one unit, the mean age of the blood units was used as the exposure. The median of the mean age of blood units transfused per patient was 11 days [interquartile range, 8, 15] in the freshest available blood group and 23 days [interquartile range, 17, 30] in the oldest available blood group. In the primary analysis, posttransfusion acute kidney injury was observed in 688 of 4,777 (14.4%) patients given the freshest available blood and 1,487 of 9,684 (15.4%) patients given the oldest available blood, with an estimated relative risk (95% CI) of 0.94 (0.86 to 1.02; P = 0.132). The secondary analysis treated blood age as a continuous variable (defined as duration of storage in days), with an estimated relative risk (95% CI) of 1.00 (0.96 to 1.04; P = 0.978) for a 10-day increase in the mean age of erythrocyte units. CONCLUSIONS In a population of patients without severely impaired baseline renal function receiving fewer than 10 erythrocyte units, duration of blood storage had no effect on the incidence of posttransfusion acute kidney injury.

Abstract

BACKGROUND Standard first-step therapy for Kawasaki disease consists of Intravenous immunoglobulin and high dose Aspirin (80-100 mg/kg/day). The standard dose of Intravenous immunoglobulin (2gr/kg) is strongly effective in reducing the risk of coronary arteries abnormalities. So, the proper dose and efficacy of Aspirin to decrease the risk of coronary arteries abnormalities is a controversial issue. In this study, it is tried to assess the result of eliminating high-dose Aspirin in the treatment of the acute phase of Kawasaki and observe the incidence rate of coronary arteries abnormalities when only Intravenous immunoglobulin was administered. METHODS This study is a prospective randomized, open-label, blinded end-points clinical trial performed in Afzalipour hospital in Kerman University of Medical Sciences from September 2017 to September 2018 in 62 patients with typical and atypical Kawasaki disease. The study group received Intravenous immunoglobulin (2 g/kg) and the control group get the same dose of Intravenous immunoglobulin plus Aspirin with the dose of 80-100 mg/Kg/day until they were afebrile for 48 hours. Afterward, both groups received a daily single dose (3-5 mg/kg) of Aspirin for six weeks. Echocardiography was done after two weeks, six weeks, and six months. Internal diameter of the left and right main coronary arteries was measured and then the corresponding Z-score was calculated. RESULTS In the study group, coronary arteries abnormalities decreased from 38.7% in the 2nd week to 16.1% in the 6th month. In the control group, it declined from 54.8% to 22.6%. There was no statistically significant difference between the groups in term of frequency of abnormal coronary arteries at the study period (P=0.151). CONCLUSIONS We concluded that high dose Aspirin does not have a significant role in preventing coronary arteries abnormalities in Kawasaki disease and giving standard 2 gr/kg/day Intravenous immunoglobulin without high-dose Aspirin in acute-phases therapy does not increase the risk of coronary arteries abnormality.