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1.
Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study
Liu X, Zhou H, Hu Y, Yin J, Li J, Chen W, Huang R, Gong Y, Luo C, Mei H, et al
The Lancet. Haematology. 2023
Abstract
BACKGROUND Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 10(9) platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING HUTCHMED.
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An innovated elastic compression hemostasis technique for extremity excision in patients with extensive burns: A prospective clinical randomized controlled trial
Shen C, Liu X, Zhang B, Cai J, Sun T, Li D, Deng H, Yuan H
Surgery. 2023
Abstract
OBJECTIVE To introduce an innovative elastic compression hemostasis technique for extremity excision in extensively burnt patients and investigate its effectiveness. METHODS Ten patients were included and divided into 2 groups: the control group (4 patients, 12 extremities) receiving the conventional hemostasis technique and the experimental group (6 patients, 14 extremities) receiving the innovative technique. General data of the patients were collected, excision size measured, hemostasis time recorded, average blood loss per 1% total body surface area of the excised wound calculated, incidence of subcutaneous hematoma and take rate determined. RESULTS The 2 groups had no statistical difference in the baseline data. Average blood loss per 1% total body surface area of the excised wound in the upper and the lower extremities was (62.1 ± 11.5) mL and (35.6 ± 11.0) mL in the experimental group, significantly less than (94.3 ± 6.9) mL and (82.3 ± 6.2) mL in the control group; a reduction of 34.1% and 56.8% respectively. Hemostasis time in the upper and the lower extremities were (5.0 ± 0.7) min/1% total body surface area and (2.6 ± 0.3) min/1% total body surface area, respectively, in the experimental group, significantly less than (7.4 ± 0.6) min/1% total body surface area and (4.0 ± 0.9) min/1% total body surface area in the control group; a reduction of 31.8% and 34.9% respectively. The incidences of subcutaneous hematoma were 7.1% and 8.3%, and the take rate (85.9 ± 6.0)% and (86.5 ± 4.8)% in the experimental and the control group, respectively, with no statistically significant differences. CONCLUSION The innovative elastic compression hemostasis technique is a reliable new method that significantly reduces blood loss during extremity excision in patients with extensive burns and is worth wider understanding and application.
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Peri-articular administration of tranexamic acid is an alternative route in total knee arthroplasty: a systematic review and meta-analysis
Fan D, Ma J, Liu X, Zhang L
Journal of orthopaedic surgery and research. 2022;17(1):211
Abstract
BACKGROUND As an antifibrinolytic agent, tranexamic acid (TXA) is increasingly used in total knee arthroplasty (TKA) to reduce blood loss. The administration of intravenous and intra-articular TXA has been well explored, but the most efficient way to administer TXA remains in question. Peri-articular injection (PAI) of TXA is a recently mentioned method. A meta-analysis of the efficacy of PAI TXA in patients after TKA should be performed. METHODS A systematic search was performed within PubMed, Embase, and the Cochrane Library up to November 8, 2021. Two authors independently screened studies for eligibility and extracted data for analysis. The primary outcome was haemoglobin change. The secondary outcomes were haematocrit change, total drainage volume, thromboembolic events, and blood transfusion. RESULTS A total of ten studies were included in this meta-analysis. The results indicated that there was a significant decrease in haemoglobin change when using PAI TXA compared with no TXA (mean difference - 1.05; 95% CI - 1.28 to - 0.81; P < 0.00001; I(2) = 0%), but it had no significant differences compared with IA and IV (mean difference - 0.01; 95% CI - 0.17 to - 0.14; P = 0.85; I(2) = 39%). There were no significant differences between the TXA < 1.5 g subgroup (0.10, 95% CI - 0.27 to 0.46; P = 0.60; I(2) = 0%) and the TXA ≥ 1.5 g subgroup (0.18, 95% CI - 0.12 to 0.48; P = 0.24; I(2) = 74%). In addition, the combined group (PAI plus IV or IA) was superior to the IV or IA group in terms of haemoglobin change (mean difference - 0.51; 95% CI - 0.76 to - 0.27; P < 0.0001; I(2) = 19%). Regarding haematocrit change, the pooled result showed it was significantly less in the PAI group than the non-TXA group. Similarly, comparing it against the IV subgroup, the result revealed a difference in favour of the PAI group, with a mean difference of - 1.89 g/dL (95% CI - 2.82 to - 0.95; P < 0.0001; I(2) = 67%). For total drainage volume, the pooled result was in favour of PAI TXA over no TXA (297 ml, 95% CI - 497.26 to - 97.23; P = 0.004; I(2) = 87%), but it had no significant difference compared with IA and IV (mean difference - 37.98; 95% CI - 115.68 to 39.71; P = 0.34; I(2) = 95%). There was no significant difference in thromboembolic events (OR 0.74; 95% CI 0.25 to 2.21; P = 0.59; I(2) = 0%). Blood transfusion was not significantly different between the PAI group and the non-TXA group (OR 0.50; 95% CI 0.23 to 1.06; P = 0.07; I(2) = 21%), and there was no significant difference between PAI and the other two TXA injection methods (OR 0.72; 95% CI 0.41 to 1.25; P = 0.24; I(2) = 19%). CONCLUSION PAI has comparable effects to IV and IA injections. PAI is an alternative injection route of TXA for patients who have undergone TKA.
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Efficacy and safety of vadadustat compared to darbepoetin alfa on anemia in patients with chronic kidney disease: a meta-analysis
Huang Q, Liao Z, Liu X, Xia Y, Wang J
International urology and nephrology. 2022
Abstract
OBJECTIVE As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD). METHODS Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs). RESULTS Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively). CONCLUSION Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.
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Endoscopic Delivery of Polymers Reduces Delayed Bleeding after Gastric Endoscopic Submucosal Dissection: A Systematic Review and Meta-Analysis
Chen Y, Zhao X, Wang D, Liu X, Chen J, Song J, Bai T, Hou X
Polymers. 2022;14(12)
Abstract
New endoscopic approaches for the prevention of delayed bleeding (DB) after gastric endoscopic submucosal dissection (ESD) have been reported in recent years, and endoscopic delivery of biodegradable polymers for iatrogenic ulcer hemostasis and coverage has emerged as one of the most promising techniques for post-ESD management. However, the comparative efficacy of these techniques remains uncertain. We performed a systematic search of multiple databases up to May 2022 to identify studies reporting DB rates as outcomes in patients undergoing gastric ESD who were treated with subsequent endoscopic management, including endoscopic closure (clip-based methods and suturing), PGA sheet tissue shielding, and hemostatic powder/gel spray (including polymeric sealants and other adhesives). The risk ratios (RRs) of delayed bleeding in treatment groups and control groups were pooled, and the Bayesian framework was used to perform a network meta-analysis (NMA). Among these studies, 16 head-to-head comparisons that covered 2742 lesions were included in the NMA. Tissue shielding using PGA sheets significantly reduced the risk of DB by nearly two thirds in high-risk patients, while hemostatic spray systems, primarily polymer-based, reduced DB in low-risk patients nine-fold. Researchers should recognize the essential role of polymers in the management of ESD-induced ulcers, and develop and validate clinical application strategies for promising materials.
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A multicenter, prospective, randomized clinical study to evaluate the efficacy and safety of fibrin sealant as an adjunct to sutured dural repair
Yu R, Zhu W, Kocharian R, Ilie B, Wang Z, Kang D, Zhao G, Yang H, Shu K, Liu X, et al
Chinese medical journal. 2022;135(20):2506-2508
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Safety and Efficacy of Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials
Ren J, Qian D, Wu J, Ni L, Qian W, Zhao G, Huang C, Liu X, Zou Y, Xing W
Frontiers in neurology. 2021;12:710495
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Editor's Choice
Abstract
BACKGROUND In recent decades, tranexamic acid (TXA) antifibrinolytic therapy before aneurysm clipping or embolization has been widely reported, but its safety and efficacy remain controversial. This meta-analysis evaluated the efficacy and safety of TXA therapy in aneurysmal subarachnoid hemorrhage (aSAH) patients, aiming to improve the evidence-based medical knowledge of treatment options for such patients. METHODS Pubmed, Web of Science, and Cochrane Library databases were searched up to 1 March 2021 for randomized controlled trials (RCTs). We extracted safety and efficacy outcomes and performed a meta-analysis using the Review Manager software. We performed two group analyses of TXA duration and daily dose. RESULTS Ten RCT studies, enrolling a total of 2,810 participants (1,410 with and 1,400 without TXA therapy), matched the selection criteria. In the TXA duration group: TXA did not reduce overall mortality during the follow-up period [RR 1.00 (95% CI 0.81-1.22)]. The overall rebleeding rate in the TXA group was 0.53 times that of the control group, which was statistically significant [RR 0.53 (95% CI 0.39-0.71)]. However, an RR of 0.43 was not statistically significant in the subgroup analysis of short-term therapy [RR 0.43 (95% CI 0.13-1.39)]. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group [RR 1.13 (95% CI 1.02-1.24)]. However, the trend was not statistically significant in the subgroup analysis [short-term: RR 1.10 (95% CI 0.99-1.23); long-term: RR 1.22 (95% CI 0.99-1.50)]. Treatment with TXA did not cause significant delayed cerebral ischemia [RR 1.18 (95% CI 0.89-1.56)], and its subgroup analysis showed an opposite and insignificant effect [short-term: RR 0.99 (95% CI 0.79-1.25); long-term: RR 1.38 (95% CI 0.86-2.21)]. Results in the daily dose group were consistent with those in the TXA duration group. CONCLUSIONS Tranexamic acid does not reduce overall mortality in patients with aSAH, nor does it increase the incidence of delayed cerebral ischemia. Tranexamic acid in treating aSAH can reduce the incidence of rebleeding. However, there is no statisticalsignificance in the ultra-early short-term and low daily dose TXA therapy, which may be due to the lack of relevant studies, and more RCT experiments are needed for further study. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/display_record.asp? PROSPERO, identifier: 244079.
PICO Summary
Population
Aneurysmal subarachnoid haemorrhage patients (10 studies, n= 2,810).
Intervention
Tranexamic acid (TXA), (n= 1,410).
Comparison
Conventional treatment without TXA (n= 1,400).
Outcome
The overall re-bleeding rate in the TXA group was 0.53 times that of the control group. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group. Treatment with TXA did not cause significant delayed cerebral ischemia.
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A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia
Mei H, Liu X, Li Y, Zhou H, Feng Y, Gao G, Cheng P, Huang R, Yang L, Hu J, et al
Journal of hematology & oncology. 2021;14(1):37
Abstract
BACKGROUND Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. METHODS Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 10(9)/L) after 8 weeks of treatment. RESULTS The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83-68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39-86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. CONCLUSIONS In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843 , registered July 19, 2017, retrospectively registered.
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Early intravenous tranexamic acid intervention reduces post-traumatic hidden blood loss in elderly patients with intertrochanteric fracture: a randomized controlled trial
Ma H, Wang H, Long X, Xu Z, Chen X, Li M, He T, Wang W, Liu L, Liu X
Journal of orthopaedic surgery and research. 2021;16(1):106
Abstract
PURPOSE Elderly patients with intertrochanteric fractures exhibit post-traumatic hidden blood loss (HBL). This study aimed to evaluate the efficacy and safety of reducing post-traumatic HBL via early intravenous (IV) tranexamic acid (TXA) intervention in elderly patients with intertrochanteric fracture. METHODS A prospective randomized controlled study was conducted with 125 patients (age ≥ 65 years, injury time ≤ 6 h) who presented with intertrochanteric fracture from September 2018 and September 2019. Patients in the TXA group (n = 63) received 1 g of IV TXA at admission, whereas those in the normal saline (NS) group (n = 62) received an equal volume of saline. Hemoglobin (Hgb) and hematocrit (Hct) were recorded at post-traumatic admission (PTA) and on post-traumatic days (PTDs) 1-3. HBL was calculated using the Gross formula. Lower extremity venous ultrasound was performed to detect venous thrombosis. RESULTS Hgb on PTDs 2 and 3 was statistically higher in the TXA group than in the NS group. Hct and HBL on PTDs 1-3 were significantly less in the TXA group compared to the NS group. Preoperative transfusion rate was significantly lower in the TXA group compared with the NS group. There was no difference between the two groups with regard to the rates of complications. CONCLUSION Early IV TXA intervention could reduce post-traumatic HBL and pre-operative transfusion rate in elderly patients with intertrochanteric fractures without increasing the risk of venous thrombosis.
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Only Tumors Angiographically Identified as Hypervascular Exhibit Lower Intraoperative Blood Loss Upon Selective Preoperative Embolization of Spinal Metastases: Systematic Review and Meta-Analysis
Gong Y, Wang C, Liu H, Liu X, Jiang L
Frontiers in oncology. 2020;10:597476
Abstract
BACKGROUND The role of preoperative embolization (PE) in reducing intraoperative blood loss (IBL) during surgical treatment of spinal metastases remains controversial. METHODS A systematic search was conducted for retrospective studies and randomized controlled trials (RCTs) comparing the IBL between an embolization group (EG) and non-embolization group (NEG) for spinal metastases. IBL data of both groups were synthesized and analyzed for all tumor types, hypervascular tumor types, and non-hypervascular tumor types. RESULTS In total, 839 patients in 11 studies (one RCT and 10 retrospective studies) were included in the analysis. For all tumor types, the average IBL did not differ significantly between the EG and NEG in the RCT (P = 0.270), and there was no significant difference between the two groups in the retrospective studies (P = 0.05, standardized mean difference [SMD] = -0.51, 95% confidence interval [CI]: -1.03 to 0.00). For hypervascular tumors determined as such by consensus (n = 542), there was no significant difference between the two groups (P = 0.52, SMD = -0.25, 95% CI: -1.01 to 0.52). For those determined as such using angiographic evidence, the IBL was significantly lower in the EG than in the NEG group, in the RCT (P = 0.041) and in the retrospective studies (P = 0.004, SMD = -0.93, 95% CI: -1.55 to -.30). For IBL of non-hypervascular tumor types, both the retrospective study (P = 0.215) and RCT (P = 0.947) demonstrated no statistically significant differences in IBL between the groups. CONCLUSIONS Only tumors angiographically identified as hypervascular exhibited lower IBL upon PE in this study. Further exploration of non-invasive methods to identify the vascularity of tumors is warranted.