Abstract

BACKGROUND Nafamostat mesilate (NM), a broad-spectrum and potent serine protease inhibitor, can be used as an anticoagulant during extracorporeal circulation, as well as a promising drug effective against coronavirus disease 2019 (COVID-19). We conducted a systematic meta-analysis to evaluate the safety and efficacy of NM administration in critically ill patients who underwent blood purification therapy (BPT). METHODS The Cochrane Library, Web of Science and PubMed were comprehensively searched from inception to August 20, 2021, for potential studies. RESULTS Four randomized controlled trials (RCTs) and seven observational studies with 2723 patients met the inclusion criteria. The meta-analysis demonstrated that conventional therapy (CT) significantly increased hospital mortality compared with NM administration (RR = 1.25, p = 0.0007). In subgroup analyses, the in-hospital mortality of the NM group was significantly lower than that of the anticoagulant-free (NA) group (RR = 1.31, p = 0.002). The CT interventions markedly elevated the risk ratio of bleeding complications by 45% (RR = 1.45, p = 0.010) compared with NM interventions. In another subgroup analysis, NM used exhibited a significantly lower risk of bleeding complications than those of the low-molecular-weight heparin (LMWH) used (RR = 4.58, p = 0.020). The filter lifespan was decreased significantly (MD = -10.59, p < 0.0001) in the NA groups compared with the NM groups. Due to the poor quality of the included RCTs, these results should be interpreted with caution. CONCLUSION Given the better survival outcomes, lower risk of bleeding, NM anticoagulation seems to be a safe and efficient approach for BPT patients and could yield a favorable filter lifespan. More multi-center RCTs with large samples are required for further validation of this study.

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.

Abstract

ImportanceConvalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed ObjectiveTo evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19 Design, Setting, and ParticipantsOpen-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020 The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation) The trial was terminated early after 103 of a planned 200 patients were enrolled InterventionConvalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity Main Outcomes and MeasuresPrimary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]) Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours ResultsOf 103 patients who were randomized (median age, 70 years;60 [58 3%] male), 101 (98 1%) completed the trial Clinical improvement occurred within 28 days in 51 9% (27/52) of the convalescent plasma group vs 43 1% (22/51) in the control group (difference, 8 8% [95% CI, −10 4% to 28 0%];hazard ratio [HR], 1 40 [95% CI, 0 79-2 49];P =  26) Among those with severe disease, the primary outcome occurred in 91 3% (21/23) of the convalescent plasma group vs 68 2% (15/22) of the control group (HR, 2 15 [95% CI, 1 07-4 32];P =  03);among those with life-threatening disease the primary outcome occurred in 20 7% (6/29) of the convalescent plasma group vs 24 1% (7/29) of the control group (HR, 0 88 [95% CI, 0 30-2 63];P =  83) (Pfor interaction =  17) There was no significant difference in 28-day mortality (15 7% vs 24 0%;OR, 0 65 [95% CI, 0 29-1 46];P =  30) or time from randomization to discharge (51 0% vs 36 0% discharged by day 28;HR, 1 61 [95% CI, 0 88-2 93];P =  12) Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87 2% of the convalescent plasma group vs 37 5% of the control group (OR, 11 39 [95% CI, 3 91-33 18];P <  001) Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care Conclusion and RelevanceAmong patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference Trial RegistrationChinese Clinical Trial Registry:ChiCTR2000029757

Abstract

This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 10(9)/L and 80 × 10(9)/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 10(9)/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 10(9)/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit-risk ratio in Chinese chronic ITP patients. Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761.

Abstract

Importance: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective: To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants: Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention: Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures: Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results: Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care. Conclusion and Relevance: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000029757.

Abstract

OBJECTIVE To observe the efficacy of intravenous, topical and combined application of tranexamic acid (TXA) in patients with thoracolumbar fracture fixed with percutaneous pedicle screw, and to identify the optimal application method of TXA. METHODS A total of 181 thoracolumbar fracture patients treated with percutaneous pedicle screw fixation were enrolled in the current randomized controlled clinical trial, and were randomly classified as three groups, including group A (intravenous group), group B (topical group), and group C (combined group). At the same time, the total blood loss (TBL), hidden blood loss (HBL), intraoperative blood loss (IBL), preoperative d-dimer, postoperative d-dimer, incidence of deep vein thrombosis (DVT) and other complications were compared and analyzed among these three groups. RESULTS TBL, HBL and IBL in topical group 24 h after operation were higher (P<0.05) than those in intravenous group and combined group, while the difference between intravenous group and combined group was not statistically significant. Meanwhile, there was no statistically significant difference in operation time, preoperative d-dimer and postoperative d-dimer among these three groups (P>0.05), but d-dimer in all the three groups at 72 h after surgery was higher than that before surgery. No DVT or other complication was observed in all patients. CONCLUSIONS Preoperative intravenous drip of TXA can remarkably reduce the intraoperative HBL and IBL in thoracolumbar fracture patients fixed with percutaneous pedicle screw. Nonetheless, intraoperative topical application of TXA before wound closure is not recommended.

Abstract

OBJECTIVES The great majority of adult patients with immune thrombocytopenia (ITP) who fail to respond to first-line medication or who relapse following response require additional treatment. Although broad guidelines currently exist for second-line and subsequent therapies, none to date have been prescriptive. The purpose of this systematic review and network meta-analysis was to establish a clinically relevant ranking of the efficacy and safety of medications for adults (≥18 years old) with previously treated ITP. METHODS Relevant publications from Medline, Embase, and the Cochrane database were searched from their inceptions through July 31, 2018. The primary outcome was the overall response (OR, defined as a platelet count ≥50 x 10(9)/L at the end of treatment without rescue therapy), while the secondary endpoints included early response (ER; i.e. a platelet count ≥50 x 10(9)/L at week 2 after initiation of treatment) and therapy-related severe adverse events (AEs). RESULTS Thirteen randomized controlled trials (1,202 patients) were included in this study. According to pooled results, romiplostim appears to be the most suitable treatment in terms of OR, followed by avatrombopag, eltrombopag, fostamatinib, and rituximab. Avatrombopag produced more satisfactory outcomes than romiplostim, eltrombopag, and rituximab in terms of ER; severe AEs profiles were similar across all treatment arms. CONCLUSION Romiplostim appears to be the best option for patients who fail to respond to prior treatment or relapse thereafter, while avatrombopag and eltrombopag are reasonable alternatives. Rituximab monotherapy is not recommended, as it produces the lowest OR and ER rates.

Abstract

BACKGROUND Anemia is extremely common among dialysis patients and underlies some of the symptoms associated with reduced kidney function, including fatigue, depression, reduced exercise tolerance, and dyspnea. OBJECTIVES A clearer cognition of the prognosistic impact of hemoglobin (Hb) or hematocrit (Hct) target for the outcomes of dialysis patients is urgent. This article aims to establish the suitable hemoglobin in order to provide clinical guidance. METHODS MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather randomized controlled trials that assessed all-cause mortality, cardiovascular events, fistula thrombosis, infectious diseases and transfusion among dialysis-dependent patients using erythropoiesis-stimulating agents. The meta-analysis was accomplished via Revman 5.3 version. FINDINGS Totally, nine eligible studies were included, with study subjects involving 3228 patients. There was a significantly higher risk of fistula thrombosis without heterogeneity (RR 1.34, 95% CI 1.15-1.55; p < 0.05) in the higher Hb target group than in the lower Hb target group in the fixed effects model. However, no significant difference was found in all-cause mortality in the fixed effects model (RR 1.09, 95% CI 0.93-1.27; p = 0.30), cardiovascular events (RR 0.77, 95% CI 0.31-1.92; p = 0.58), infectious diseases (RR 0.69, 95% CI 0.24-1.96; p = 0.49) and transfusion (RR 0.92, 95% CI 0.42-1.99; p = 0.82) in the random effects model between the higher Hb target group and the lower Hb target group. DISCUSSION The results favor lower Hb target. To target lower Hb target when treating dialysis patients with anemia may decrease the risk of fistula thrombosis without increasing the risk of death, cardiovascular events, infectious diseases and transfusion.

Abstract

Eltrombopag, a thrombopoietin receptor agonist, raises platelet counts and reduces bleeding in patients with immune thrombocytopenia (ITP). In Chinese patients, eltrombopag was evaluated at an initial dose of 25 mg, vs. 50 mg for non-Asians, because the plasma exposure of eltrombopag is higher in East Asians. A multicentre, double-blind, randomised, placebo-controlled, 8-week, phase III study enrolled 155 patients with chronic, previously treated ITP. Dosage could be adjusted (25-75 mg/day) to maintain platelet counts 50-250 x 109 /l. The primary efficacy endpoint was the proportion of patients with a platelet count ≥50 x 109 /l after Day 42. Pharmacokinetics and pharmacodynamics of eltrombopag were analysed in an open-label extension. After Day 42, 57.7% of eltrombopag-treated and 6.0% of placebo-treated patients achieved platelet counts ≥50 x 109 /l. Odds of achieving a platelet count ≥50 x 109 /l were 26.08 times greater with eltrombopag than placebo (P < 0.001). Compared with placebo, time to response and duration of response were better with eltrombopag (P < 0.001) and the odds of any bleeding were reduced by 72% (P = 0.001). Tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics were similar to previous findings in East Asian patients. In conclusion, in Chinese patients with chronic ITP, eltrombopag 25 mg once daily, elevated platelet counts to a safe range and reduced bleeding.

Abstract

BACKGROUND BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. OBJECTIVES To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. PATIENTS/METHODS In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12-65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. RESULTS Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean +/- SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 +/- 7.2; 3-times-weekly, 4.3 +/- 6.5; combined, 4.9 +/- 6.8) vs. on-demand treatment (57.7 +/- 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. CONCLUSIONS Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.