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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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Effectiveness comparisons of drug therapies for postoperative aneurysmal subarachnoid hemorrhage patients: network meta‑analysis and systematic review
Yu W, Huang Y, Zhang X, Luo H, Chen W, Jiang Y, Cheng Y
BMC neurology. 2021;21(1):294
Abstract
OBJECTIVE To compare the effectiveness of various drug interventions in improving the clinical outcome of postoperative patients after aneurysmal subarachnoid hemorrhage (aSAH) and assist in determining the drugs of definite curative effect in improving clinical prognosis. METHODS Eligible Randomized Controlled Trials (RCTs) were searched in databases of PubMed, EMBASE, and Cochrane Library (inception to Sep 2020). Glasgow Outcome Scale (GOS) score, Extended Glasgow Outcome Scale (GOSE) score or modified Rankin Scale (mRS) score was used as the main outcome measurements to evaluate the efficacy of various drugs in improving the clinical outcomes of postoperative patients with aSAH. The network meta-analysis (NMA) was conducted based on a random-effects model, dichotomous variables were determined by using odds ratio (OR) with 95% confidence interval (CI), and a surface under the cumulative ranking curve (SUCRA) was generated to estimate the ranking probability of comparative effectiveness among different drug therapies. RESULTS From the 493 of initial citation screening, forty-four RCTs (n = 10,626 participants) were eventually included in our analysis. Our NMA results showed that cilostazol (OR = 3.35,95%CI = 1.50,7.51) was the best intervention to improve the clinical outcome of patients (SUCRA = 87.29%, 95%CrI 0.07-0.46). Compared with the placebo group, only two drug interventions [nimodipine (OR = 1.61, 95%CI 1.01,2.57) and cilostazol (OR = 3.35, 95%CI 1.50, 7.51)] achieved significant statistical significance in improving the clinical outcome of patients. CONCLUSIONS Both nimodipine and cilostazol have exact curative effect to improve the outcome of postoperative patients with aSAH, and cilostazol may be the best drug to improve the outcome of patients after aSAH operation. Our study provides implications for future studies that, the combination of two or more drugs with relative safety and potential benefits (e.g., nimodipine and cilostazol) may improve the clinical outcome of patients more effectively.
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The therapeutic value of arthroscopic microfracture technique in combination with platelet-rich plasma injection for knee cartilage injury
Yang Z, Wu Y, Yin K, Xiang J, Liu C, Chen W, Dai Z
American journal of translational research. 2021;13(4):2694-2701
Abstract
OBJECTIVE The purpose of this study was to analyze the efficacy of platelet-rich plasma (PRP) injection combined with arthroscopic microfracture technique for knee cartilage injury. METHODS Seventy-nine patients with knee cartilage injury were randomly divided into a control group (CG, n=39) and an observation group (OBG, n=40). Both of the groups were treated with the arthroscopic microfracture technique, and the OBG was additionally treated with PRP injection. RESULTS The VAS scores for pain in the affected area of the OBG were lower than those of the CG at 1, 3, 5, and 7 days after surgery (P < 0.05). Knee flexion, hyperextension, and rotation angles in the OBG were greater than those in the CG at 1 month after surgery (P < 0.05). IKDC scores in the OBG were lower than those in the CG at 1, 2, and 3 weeks after surgery (P < 0.05). The Tegner and Lysholm scores in the OBG were higher than those in the CG at 1, 2, and 3 months after surgery (P < 0.05). The complication rate in the OBG was 10.00%, which was lower than that of 28.21% in the CG (P < 0.05). CONCLUSION The efficacy of microfracture technique combined with PRP injection in the treatment of knee joint cartilage injury is significantly improved compared with that of microfracture technique alone, which can reduce postoperative complications and improve the range of motion and function of the knee joint.
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Low-dose PPI to prevent bleeding after ESD: A multicenter randomized controlled study
Yang L, Qi J, Chen W, Guo Q, Xie R, Zhao Z, Qin S, Liu A, Den M, Fan C, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;136:111251
Abstract
BACKGROUND Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. METHODS This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. RESULTS 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3-9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9-9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (-4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). CONCLUSION The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.
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The effect of adjunctive intravitreal conbercept at the end of diabetic vitrectomy for the prevention of post-vitrectomy hemorrhage in patients with severe proliferative diabetic retinopathy: a prospective, randomized pilot study
Jiang T, Gu J, Zhang P, Chen W, Chang Q
BMC ophthalmology. 2020;20(1):43
Abstract
BACKGROUND To investigate the effect of intravitreal conbercept (IVC) injections on the incidence of postoperative vitreous hemorrhage (VH) in eyes undergoing surgery for severe proliferative diabetic retinopathy. METHODS This was a pilot prospective, comparative, and randomized study. Thirty patients, who underwent vitrectomy for severe proliferative diabetic retinopathy, were assigned randomly to either group 1 (intravitreal conbercept [IVC] injection at the end of pars plana vitrectomy) or group 2 (no IVC injection). Postoperative follow-up was performed on the first day, first week, first month, third month, sixth month and first year after surgery. The primary outcome was the incidence of postoperative VH. Secondary outcomes were the initial time of vitreous clearing (ITVC), best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after surgery. RESULTS A total of 30 eyes, from 30 patients, were included. Fifteen eyes were enrolled in the IVC group and fifteen in the control group. The incidence of early and late postoperative VH was not significantly different between the control and IVC groups. ITVC was shorter in the IVC group than that in the control group, but this was not significant (7.38 +/- 10.66 vs 13.23 +/- 17.35, P = 0.31). Final BCVA, 1 year after surgery, showed significant improvement compared to baseline in both groups. However, analysis of the BCVA at any postoperative visit after surgery showed no significant differences between the two groups. There were two cases of recurrent VH identified at 3 and 6 months after surgery in each group, requiring a second round of surgery. Foveal thickness was significantly different between the two groups at the 3-month, 6-month and 1-year follow-up visits. CONCLUSIONS In this pilot study, the effect of IVC injection in reducing the incidence of postoperative VH after diabetic vitrectomy at the end of vitrectomy was not shown. TRIAL REGISTRATION The study was registered with the Chinese Clinical Trial Registry. (Reference Number: ChiCTR1800015751).
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Postoperative outcomes of tranexamic acid use in geriatric trauma patients treated with proximal femoral intramedullary nails: A systematic review and meta-analysis
Xing F, Chen W, Long C, Huang F, Wang G, Xiang Z
Orthopaedics & traumatology, surgery & research : OTSR. 2020
Abstract
BACKGROUND Recently, there has been a series of clinical studies focusing on the perioperative administration of tranexamic acid (TXA) in geriatric trauma patients undergoing proximal femoral intramedullary nail surgery. However, the safety and efficacy of TXA in these patients remains controversial. Therefore, we performed a systematic review to focus on two questions: (1) would TXA reduce perioperative blood loss in geriatric trauma patients undergoing proximal femoral intramedullary nail surgery? and (2) would TXA increase the rate of perioperative complications in geriatric trauma patients undergoing proximal femoral intramedullary nail surgery? PATIENTS AND METHODS We systematically searched electronic databases (MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials) up to April 20, 2019. The perioperative blood loss and complication data were extracted and analysed by RevMan Manager 5.3. RESULTS Finally, five randomized controlled studies, involving 539 geriatric intertrochanteric fracture patients undergoing proximal femoral intramedullary nail surgery, were enrolled in this systematic review. Compared with the control group, the TXA group had significantly lower total perioperative blood loss (WMD=-172.84; 95% CI, -241.44 to -104.24; I(2)=0%), intraoperative blood loss (WMD=-34.20; 95% CI, -46.04 to -22.36; I(2)=0%), total perioperative hidden blood loss (WMD=-139.05; 95% CI, -213.67 to -64.43; I(2)=0%), perioperative transfusion rates (RR =-0.16; 95% CI, -0.24 to -0.08; I(2)=22%), length of hospital stay (WMD=-1.18; 95% CI, -1.91 to -0.46; p=0.001; I2=12%), and postoperative wound haematoma rates (RD=-0.05; 95% CI, -0.09 to 0.00; p=0.03; I(2)=0%). In addition, there were no significant differences between TXA and control groups in the terms of surgical time, postoperative mortality, total thromboembolic events, wound infections, cerebrovascular accidents, respiratory infections, and renal failure. DISCUSSION TXA in geriatric trauma patients undergoing intramedullary nail surgery is effective for perioperative haemostasis without increasing the incidence of postoperative complications. LEVEL OF EVIDENCE II, Systematic review and Meta-analysis.
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A randomised controlled trial of fibrinogen concentrate during scoliosis surgery
Chen W, Shen J, Zhang Y, Hu A, Liang J, Ma L, Yu X, Huang Y
Anaesthesia. 2020
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Abstract
Bleeding and blood transfusion are common after scoliosis surgery. Fibrinogen is essential for blood clot formation and depletes quickly during haemorrhage. We randomly allocated 102 children 12-18 years old having surgery for idiopathic scoliosis, 51 to intra-operative fibrinogen concentrate 30 mg.kg(-1) (maximum 2 g) and 51 to saline placebo. Fibrinogen reduced peri-operative blood loss by a median (95%CI) volume of 155 (5-320) ml, from a median (IQR [range]) of 1035 (818-1420 [400-3030]) ml to 885 (755-1155 [270-2645]) ml, p = 0.04. Seven and four children received allogeneic red blood cell transfusion after fibrinogen and placebo, respectively, p = 0.34. There were no side-effects.
PICO Summary
Population
Patients between 12 to 18 years old having surgery for idiopathic scoliosis (n= 102).
Intervention
Intraoperative fibrinogen concentrate (30 mg.kg−1, maximum 2 g), (n= 51).
Comparison
Saline placebo (n= 51).
Outcome
Fibrinogen concentrate infusion reduced median perioperative bleeding by about 155ml compared with placebo. Fibrinogen did not reduce postoperative blood transfusion or increase postoperative haemoglobin concentration.
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Motherwort injection for preventing postpartum hemorrhage in pregnant women with cesarean section: A systematic review and meta-analysis
Chen W, Yu J, Tao H, Cai Y, Li Y, Sun X
Journal of Evidence-Based Medicine. 2018;11((4):):252-260
Abstract
OBJECTIVE To assess the impact of motherwort injection alone or combined with oxytocin for preventing postpartum hemorrhage in pregnant women with caesarean section. METHODS A systematic review and meta-analysis of randomized trials were performed. PubMed, EMbase, The Cochrane Central Register of Controlled Trials (CENTRAL), Chinese database Sino-Med, Chinese National Knowledge Infrastructure Database (CNKI), VIP Chinese Science and Technique Journals Database, WanFang, and ClinicalTrials.gov were searched. Randomized controlled trials (RCTs) that compared motherwort injection alone or motherwort injection combined with oxytocin in pregnant women receiving cesarean section were included. Paired reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias, and extracted data. We performed random-effects meta-analyses of RCTs along with a limited number of prespecified subgroup hypotheses, and sensitivity analyses were carried out with other statistical approaches. RESULTS Forty-six RCTs (n = 7359) proved eligible. Compared with oxytocin, both motherwort injection and motherwort injection combined with oxytocin had a significantly lower blood loss within 2 hours (MD = -21.81, 95% CI -37.05 to -6.58 and MD = -53.04, 95% CI -61.68 to -44.39); lower blood loss within 24 hours (MD = -25.44, 95% CI -39.38 to -11.51 and MD = -67.81, 95% CI -78.02 to -57.60); and lower the risk of adverse events (ORPeto 0.40, 95% CI 0.16 to 0.96 and ORPeto 0.50, 95% CI 0.35 to 0.71). Motherwort injection combined with oxytocin also decreased the risk of postpartum hemorrhage (OR 0.22, 95% CI 0.14 to 0.35.) CONCLUSIONS In pregnant women with cesarean section, motherwort injection suggests an obvious benefit and less adverse event.
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The use of adjunctive hemostatic agents in tubeless percutaneous nephrolithotomy: a meta-analysis
Wang J, Zhang C, Tan G, Yang B, Chen W, Tan D
Urolithiasis. 2014;42((6):):509-517.
Abstract
The purpose of the study was to systematically review and assess the safety and efficacy of hemostatic agents in tubeless percutaneous nephrolithotomy. Original studies on the use of hemostatic agents in tubeless percutaneous nephrolithotomy (PCNL) from January 2001 to March 2014 were searched in Ovid, Science Direct, Pubmed, and Embase by two independent reviewers. A drop in hemoglobin (Hb), analgesic requirements, length of hospital stay, and necessity for blood transfusions were compared using Review Manager 5.2. The methods were done according to the Cochrane Handbook for interventional systematic reviews and written based on the PRISMA Statement. Seven studies involving 351 patients met the inclusion criteria for the meta-analysis. The baseline characteristics were comparable in all of the studies. The results showed that the length of hospital stay was less in the experimental group than in the control group (P < 0.05). There were no significant statistical differences in terms of a drop in Hb, analgesic requirements, and the necessity for a blood transfusion between the two groups (P > 0.05). The meta-analysis indicated that the hemostatic agents in tubeless PCNL were not expected to be unsafe or mandatory, but that they were expected to be expensive. We concluded that hemostatic agents might not be necessary in tubeless PCNL.
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Is wound drainage necessary in hip arthroplasty? A meta-analysis of randomized controlled trials
Chen ZY, Gao Y, Chen W, Li X, Zhang YZ
European Journal of Orthopaedic Surgery & Traumatologie. 2014;24((6):):939-46.
Abstract
PURPOSE The use of closed suction drainage systems for hip arthroplasty (HA) is a common practice. However, the effectiveness and safety are still questionable. Thus, the aim of this meta-analysis was to review the advantages and adverse effects of closed suction drainage systems in hip arthroplasty. METHODS All randomized or quasi-randomized trials comparing the use of closed suction drainage systems with no drainage systems for hip arthroplasty were searched in PubMed, Medicine, EMBASE and other internet databases. We assessed the methodological quality of the studies and abstracted the relevant data independently. RESULTS Sixteen studies involving 1,663 participants with surgical wounds comparing HA with and without the use of drainage were included in our analysis. Our results demonstrated blood transfusion was required more frequently the same as the persistent discharge in those who received drains. No significant differences in the incidence of wound hematoma, dehiscence or deep vein thrombosis were found between those allocated to drains and the non-drained wounds. Wound infection and the range of movement of the joint after surgery were similar between the two groups. CONCLUSIONS Based on the current evidence, there is insufficient evidence to support the routine use of closed suction drainage in hip arthroplasty. At the same time, our meta-analysis study suggested that using of closed suction drainage in HA increased requirement for postoperative blood transfusion. However, there is a moderate possibility of selection bias and publication bias in this review. Because of the limited number of studies which may weaken the strength of the evidence of our results, more samples, high-quality randomized trials are needed to increase the reliability of evidences. LEVEL OF EVIDENCE II.