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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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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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The safty profile of blood salvage applied for collected blood with amniotic fluid during cesarean section
Rong X, Guo X, Zeng H, Wang J, Li M, Wang Y
BMC pregnancy and childbirth. 2022;22(1):160
Abstract
BACKGROUND The guidelines of National Health Service(NHS, the United Kingdom) recommended for use in obstetrics at increased risk of bleeding, requiring two suction devices to reduce amniotic fluid contamination, however, when comes to massive hemorrhage, it is may difficult to operate because the complex operation may delay time. The aim of the study was to detect the effect of amniotic fluid recovery on intraoperative cell salvage in obstetrics and provide evidence for clinical applications. METHOD Thirty-four patients undergoing elective cesarean section were randomly divided into two groups. In group 1, the cumulative blood from the operation field, including the amniotic fluid, was collected using a single suction device for processing. In group 2, after suctioning away the amniotic fluid using another suction device for the cumulative blood from the operation field. From each group, four samples were taken, including maternal venous blood (sample I), blood before washing (sample II), blood after washing (sample III) and blood after filtration with a leukocyte filter (sample IV), to detect serum potassium (K +), hemoglobin (Hb), white blood cell (WBC), fetal hemoglobin (HbF), alpha fetoprotein (AFP) and squamous cell (SC) levels. RESULTS The AFP, K + and WBC levels of sample III and sample IV were significantly lower than sample I in group 1 and group 2 (P < 0.05). Significantly more SCs were found in sample III than in sample I in group 1 and group 2 (P < 0.05), but SCs of sample IV had no statistical difference compared to sample I in group 1 and group 2 (P > 0.05). There was no significant difference in the K + , Hb, WBC, AFP and SC levels of sample IV between group 1 and group 2 (P > 0.05). The HbF levels of sample III and sample IV were significantly higher in group 1 than in group 2 (P < 0.05). CONCLUSION There is little or no possibility for AF contamination to enter the re-infusion system when used in conjunction with a leucodepletion filter. For maternal with Rh-negative blood, we recommend two suction devices to reduce HbF pollution. TRIAL REGISTRATION ChiCTR1800015684 , 2018.4.15.
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Effect of prophylactic central neck dissection following total thyroidectomy on surgical site wound infection, hematoma, and haemorrhage in subjects with clinically node-negative papillary thyroid carcinoma: A meta-analysis
Jin L, Liu L, Wang J, Zhang L
International wound journal. 2022
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Abstract
We performed a meta-analysis to evaluate the effect of prophylactic central neck dissection following total thyroidectomy on surgical site wound infection, hematoma, and haemorrhage in subjects with clinically node-negative papillary thyroid carcinoma. A systematic literature search up to April 2022 was performed and 3517 subjects with clinically node-negative papillary thyroid carcinoma at the baseline of the studies; 1503 of them were treated with prophylactic central neck dissection following total thyroidectomy, and 2014 were using total thyroidectomy. Odds ratio (OR) with 95% confidence intervals (CIs) were calculated to assess the effect of prophylactic central neck dissection following total thyroidectomy on surgical site wound infection, hematoma, and haemorrhage in subjects with clinically node-negative papillary thyroid carcinoma using the dichotomous method with a random or fixed-effect model. The prophylactic central neck dissection following total thyroidectomy subjects had a significantly lower surgical site wound infection (OR, 0.40; 95% CI, 0.20-0.78, P = .007) in subjects with clinically node-negative papillary thyroid carcinoma compared with total thyroidectomy. However, prophylactic central neck dissection following total thyroidectomy did not show any significant difference in hematoma (OR, 0.08; 95% CI, 0.43-2.71, P = .87), and haemorrhage (OR, 0.72; 95% CI, 0.26-1.97, P = .52) compared with total thyroidectomy in subjects with clinically node-negative papillary thyroid carcinoma. The prophylactic central neck dissection following total thyroidectomy subjects had a significantly higher surgical site wound infection, and no significant difference in hematoma, and haemorrhage compared with total thyroidectomy in subjects with clinically node-negative papillary thyroid carcinoma. The analysis of outcomes should be with caution because of the low number of studies in certain comparisons.
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Prevention of delayed post-polypectomy bleeding by prophylactic clipping after endoscopic colorectal polypectomy: a meta-analysis
Yu Z, Albéniz E, Hu J, Li P, Li Q, Hu Y, Chen J, Wang J
International journal of colorectal disease. 2022
Abstract
PURPOSE This meta-analysis aims to investigate the role of prophylactic clipping after endoscopic colorectal polypectomy or endoscopic mucosal resection (EMR) in prevention of delayed bleeding (DB) following polypectomy. METHODS We searched the PubMed, Embase, and Cochrane Library databases for randomized controlled trials comparing the effect of prophylactic clipping versus no clipping on DB since inception to 22nd April 2022. We then performed a meta-analysis using a random-effects model. RESULTS We included 8 studies with 5648 patients and 10,436 lesions. Prophylactic clipping did not reduce the overall risk of DB compared with no clipping (1.54% vs 2.05%; Log RR, -0.29; 95% confidence interval [CI], -0.59, 0.01; P = 0.06). In subgroup analyses, clipping significantly reduced DB rate in polyps ≥ 2 cm (Log RR, -0.63; 95% CI, -1.08, -0.18; P = 0.01), in non-pedunculated polyps (Log RR, -0.63; 95% CI, -1.01, -0.24; P = 0.00), and in large (≥ 2 cm) proximal polyps (Log RR, -0.81; 95% CI, -1.56, 0.05; P = 0.04), but not in polyps < 2 cm (Log RR, 0.01; 95% CI, -.40, 0.42; P = 0.95). CONCLUSION Prophylactic clipping does not prevent post-polypectomy bleeding after all EMR and should not be performed as a routine practice. Although prophylactic clipping may reduce DB rate following resection of large proximal polyps and non-pedunculated polyps, more high-quality studies are needed to determine the effects of factors such as polyp location, polyp morphology, antithrombotic drug use and complete or partial closure on the effectiveness of prophylactic clipping.
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Effect of tourniquet application on cement penetration in primary total knee arthroplasty: a meta-analysis
Yao S, Zhang W, Ma J, Wang J
Arthroplasty (London, England). 2021;3(1):29
Abstract
BACKGROUND Tourniquet application is expected to improve surgery exposure and cementation process in total knee arthroplasty (TKA) but its effectiveness remains controversial and needs to be further explored. The aim of this meta-analysis was to assess the effect of tourniquet in primary TKA. The hypothesis is that the tourniquet application affects the cement penetration in TKA. METHODS A search was conducted in PubMed, Embase, and the Cochrane Library for the potentially eligible articles. Two independent researchers reviewed the articles retrieved against the pre-designed inclusion and exclusion criteria. In primary TKA, cement penetration was assessed, and the data between the tourniquet-assisted and non-tourniquet-assisted TKAs were compared. Statistical significance was set at P < 0.05. RESULTS A total of 4 randomized controlled trials and 3 non-randomized controlled trials (involving 675 patients) were included. There was no significant difference between the tourniquet-assisted and non-tourniquet-assisted TKAs in terms of cement penetration (P > 0.05). There were no significant differences in the total surgical time, blood loss, blood transfusion, the Knee Society Score, and the visual analogue scale (VAS) between the two kinds of procedures (P > 0.05). CONCLUSIONS Tourniquet application may not affect cement penetration in primary TKA and may not help reduce blood loss, ease knee pain or improve the knee function. A surgeon may choose to use a tourniquet or not according to his or her own preference. LEVEL OF EVIDENCE Level Ib, meta-analysis.
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The efficacy and safety of topical tranexamic acid for spinal surgery: a meta-analysis
Guo T, Xuan W, Feng H, Wang J, Ma X
Current pharmaceutical design. 2021
Abstract
BACKGROUND Spinal surgeries are often accompanied by significant blood loss both intraoperatively and postoperatively. Excessive blood loss caused by surgery may lead to several harmful medical consequences. Tranexamic acid (TXA) is a kind of antifibrinolytic agent that has been widely used in spinal surgery. Currently, it is commonly accepted that intravenous TXA (ivTXA) can reduce blood loss in spinal fusion surgeries. Compared with ivTXA, topical TXA (tTXA) seems to be much easier to administer. This advantage provides a maximum concentration of TXA at the hemorrhagic site with little to no TXA entering the circulation. OBJECTIVE To evaluate the effect of tTXA on blood loss during and after spinal surgery via a comprehensive meta-analysis of the published data in randomized controlled trials (RCTs) and other comparative cohort studies. METHODS A comprehensive search of PubMed, EMBASE, the Web of Science, and the Cochrane Central Register of Controlled Trials were performed for RCTs and other comparative cohort studies on the effect of tTXA on blood loss during and after spinal surgery. The outcomes were total blood loss, hidden blood loss, intraoperative blood loss, total postoperative drainage volume, drainage tube duration postoperatively, drainage volume and drainage of blood content at postoperative day (POD) 1 and POD2, length of hospital stay, number of patients who received a blood transfusion, serum HB level at POD1, operative timespan, side effects, and complications. The final search was performed in October 2020. We followed the PRISMA guideline, and the registration number is INPLASY202160028. RESULTS In total, six studies with 481 patients were included. tTXA treatment, compared with the control conditions, can significantly reduce the total blood loss, hidden blood loss, total postoperative drainage volume, and several patients receiving blood transfusions; reduce the drainage volume and drainage of blood content at POD1; shorten the drainage tube duration postoperatively and length of hospital stay, and enhance the serum HB level at POD1 for spinal surgery. tTXA treatment did not significantly influence the intraoperative blood loss, drainage volume, or drainage of blood content at POD2 or the operative duration. CONCLUSION Compared with control conditions, tTXA has high efficacy in reducing blood loss, and drainage volume enable quick rehabilitation and has a relatively high level of safety in spinal surgery.
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The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction for reducing postoperative hemarthrosis: a prospective randomized study
Ma R, Wu M, Li Y, Wang J, Wang W, Yang P, Wang K
BMC musculoskeletal disorders. 2021;22(1):114
Abstract
BACKGROUND Hemarthrosis after anterior cruciate ligament (ACL) reconstruction can create many adverse joint effects. Tranexamic acid (TXA) can be used to minimize hemarthrosis and associated pain after ACL reconstruction. We aimed to compare the efficacies of intravenous (IV) administration and intra-articular (IA) injection of TXA during ACL reconstruction for reducing postoperative hemarthrosis. METHODS A total of 120 patients who underwent arthroscopic ACL reconstruction were included in this prospective and randomized study. All patients were randomized into three groups: IV group, IA group and placebo group. Patients in the IV group received intravenously administered TXA (15 mg/kg in 100 mL of saline solution) 10 min before tourniquet release; patients in the IA group received intra-articular TXA (15 mg/kg in 100 mL of saline solution) injected via the drainage tube; and patients in the placebo group received an equivalent volume of normal saline administered into the knee joint cavity and intravenously. Drainage tubes were removed 24 h after surgery, and all enrolled patients experienced a 4-week follow-up period. The drain output volume, visual analogue scale (VAS) score, patellar circumference, hemarthrosis grade and Lysholm score of all patients were recorded. RESULTS Both the IV group and the IA group had significantly lower drain output volumes at day 1, lower VAS scores at weeks 1 and 2, smaller patellar circumferences at weeks 1 and 2, and lower hemarthrosis grades at weeks 1 and 2 than the placebo group (p < 0.05). There were no significant differences in drain output volume, VAS score, patellar circumference or hemarthrosis grade between the IV group and the IA group at any time point (p > 0.05). No obvious differences in Lysholm score were observed between any pair of groups at week 4 (p > 0.05)). Neither infection nor deep vein thrombosis occurred in any group. CONCLUSIONS Both intravenous administration and intra-articular injection can reduce intra-articular hemarthrosis, joint pain and swelling during ACL reconstruction. No significant difference in the efficacies of reducing hemarthrosis, joint pain and swelling was found between intravenous administration and intra-articular injection. TRIAL REGISTRATION The study was registered by the Chinese Clinical Trial Registry (The comparative efficacies of intravenous administration and intra-articular injection of tranexamic acid during anterior cruciate ligament reconstruction; ChiCTR-INR-17012217 ; August 1, 2017).
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The efficacy and safety of tranexamic acid in the treatment of intertrochanteric fracture: an updated meta-analysis of 11 randomized controlled trials
Yu X, Wang J, Wang X, Xie L, Chen C, Zheng W
Journal of thrombosis and thrombolysis. 2020
Abstract
This meta-analysis was performed to investigate the efficacy and safety of tranexamic acid (TXA) in the elderly patients undergoing intertrochanteric fracture surgery from the current literatures. The electronic literature database of PubMed, Embase and Cochrane library were searched in October 2019. The intraoperative blood loss, hidden blood loss, postoperative drainage and total blood loss, postoperative hemoglobin, length of stay, transfusion rate, mortality rate, thromboembolic events and wound complications were extracted. Stata 14.0 software was used for our meta-analysis. A total of 11 RCTs (3 new RCTs in 2019) with 1202 patients met our inclusion criteria. This meta-analysis showed that administration of TXA can reduce intraoperative blood loss (P = 0.009), hidden blood loss (P = 0.000), total blood loss (P = 0.000), length of stay (P = 0.003), transfusion rate (P = 0.000) and the occurrence of wound complications (P = 0.006). Furthermore, administration of TXA was associated with an increase in the postoperative Hb level at day 1, 2 and 3 (P = 0.000, P = 0.000 and P = 0.000, respectively) after surgery. However, no significant difference was found between the TXA group and control group regarding the occurrence of thromboembolic events (P = 0.978, including deep vein thrombosis, P = 0.850; pulmonary embolism, P = 0.788; cerebrovascular accident, P = 0.549; myocardial infarction, P = 0.395) and mortality rate (P = 0. 338). Our meta-analysis suggested that administration of TXA is effective in reducing intraoperative blood loss, hidden blood loss, total blood loss, length of stay, transfusion rate, wound complications and enhancing postoperative Hb without increasing the risk of thromboembolic events and mortality rate in intertrochanteric fracture surgery. More large multi-center and high-quality RCTs are required for further research.
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Role of Xingnaojing Injection in treating acute cerebral hemorrhage: A systematic review and meta-analysis
Ma X, Wang T, Wen J, Wang J, Zeng N, Zou W, Yang Y
Medicine (Baltimore). 2020;99(15):e19648
Abstract
BACKGROUND Xingnaojing injection (XNJi) is widely used for acute cerebral hemorrhage. However, the efficacy of XNJi for acute cerebral hemorrhage has not been comprehensively proved by systematic analysis yet. Therefore, it is essential to evaluate the efficacy and safety of XNJi in an evidence-based method. METHODS Six databases were searched with XNJi used for acute cerebral hemorrhage in randomized controlled trials (RCTs). Meta-analysis was performed by Review Manager 5.3. The efficacy rate, brain edema, cerebral hematoma, neurological deficit score, hs-crp, Glasgow Coma Scale (GCS), and activities of daily living (ADL) were systematically evaluated. The Cochrane risk of bias was used to evaluate the methodological quality of eligible studies. RESULTS This study is registered with PROSPERO (CRD42018098737). Twenty-nine studies with a total of 2638 patients were included in this meta-analysis. Compared with conventional treatment, XNJi got higher efficacy rate (OR = 3.37, 95% CI [2.65, 4.28], P < .00001). Moreover, XNJi showed significant enhancement of efficacy rate via subgroup analysis in course and dosage. In addition, XNJi demonstrated significant improvement in Chinese stroke scale (CSS) and National Institutes of Health Stroke Scale (NHISS) (mean difference [MD] = -4.74, 95% CI [-5.89, -3.60], P < .00001; MD = -4.45, 95% CI [-5.49, -3.41], P < .00001), GCS (MD = 2.72, 95% CI [2.09, 3.35], P < .00001). It also remarkably decreased the level of hs-crp (MD = -6.50, 95% CI [-7.79, -5.21], P < .00001), enhanced ADL (MD = 20.38, 95% CI [17.98, 22.79], P < .00001), and alleviated hematoma and edema (MD = -2.53, 95% CI [-4.75, -0.31] P < .05; MD = -1.74 95% CI [-2.42, -1.07] P < .00001) compared with conventional treatment. CONCLUSION XNJi is effective in treating acute cerebral hemorrhage with significant improvement of CSS, NHISS and impairment of hs-crp, hematoma, and edema compared with conventional treatment. Moreover, XNJi got remarkable efficacy at the dose of 20, 30, 60 mL and from 7 to 28 days. No serious adverse reactions occurred. These results were mainly based on small-sample and low-quality studies. Therefore, more rigorous, large-scale RCTs were further needed to confirm its efficacy, safety, and detailed characteristic of application.