Incidence Of All Adverse Events Research Articles

Effectiveness and safety of empegfilgrastim (Extimia®) in patients with solid tumors receiving cytotoxic therapy: final results of the DEFENDOR study

Aim. To evaluate the effectiveness and safety of Extimia® (empegfilgrastim, JSC "BIOCAD") in reducing the frequency, duration of neutropenia, the incidence of febrile neutropenia (FN) and infections caused by FN in patients with solid tumors receiving myelosuppressive therapy. Materials and methods. The paper presents the final results of a multicenter prospective observational post-marketing study of the safety and effectiveness of Extimia® (empegfilgrastim) in patients with solid tumors receiving cytotoxic therapy. For the primary prevention of FN, all patients received empegfilgrastim at 7.5 mg subcutaneously once per course of chemotherapy (CT) 24 hours after the end of CT administration. The primary endpoint included an assessment of the relative dose-intensity (RDI) of the CT courses administered. The endpoints of interest included the assessment of the RDI of CT courses by nosology and CT regimen, the frequency of dose-limiting neutropenia, and the incidence of all adverse events (AEs) in patients who received at least one dose of the study medication, including serious AEs. Results. From February 2021 to December 2022, 3218 patients with various malignancies were included in 41 study centers of the Russian Fede- ration. Of these, 3217 (99.97%) patients received at least one dose of the study drug, and 2663 (82.8%) patients were included in the RDI evaluation population according to the study protocol. The mean age in this group was 56.9 (18–84) years. RDI ≥85% was achieved in 2,415 (90.7%) patients. The mean RDI was 96.2%, with a median of 100%. FN risk factors were present in 1216 (45.7%) patients, with age ≥65 years being the most common risk factor at 761/2663 (28.6%). It should be noted that in patients younger than 65 years, the RDI was 91.5%, and in elderly patients (≥65 years) 88.7%. Dose-limiting neutropenia was reported in 19 (0.7%) patients. There were 74 cases of grade 3–4 AEs (according to CTCAE v.5) in 59 (1.8%) patients. The most common were neutropenia, anemia, and diarrhea in 19 (0.7%), 7 (0.2%), and 6 (0.2%) patients, respectively. Serious AEs were reported in 17 patients (0.5%). Conclusion. Primary prophylaxis of FN with long-acting granulocyte colony-stimulating factor empegfilgrastim effectively maintains RDI in various nosological and therapeutic groups of patients with different CT regimens in real-world clinical practice.

Comparison of the efficacy and safety profiles of generic and branded leuprorelin acetate microspheres in patients with prostate cancer.

Leuprorelin acetate microspheres, a common gonadotropin-releasing hormone agonist, have certain clinical benefits for prostate cancer (PCa). The present study aimed to compare the efficacy and safety of generic and branded leuprorelin acetate microspheres in patients with PCa. The present retrospective, observational study included 116 patients with PCa who received generic (Boennuokang®; Beijing Biote Pharmaceutical Co., Ltd.) or branded (Enantone®; Takeda Pharmaceutical Company, Ltd.) leuprorelin acetate microspheres via injection (commonly 3.75 mg once every 4 weeks), defined as the test (n=64) and reference (n=52) groups, respectively. The present study showed that testosterone levels at month (M) 3 (P<0.001), M6 (P=0.012) and M12 (P<0.001) were decreased in the test group compared with the reference group. However, prostate-specific antigen (PSA) levels at baseline, M1, M3, M6 and M12 were not significantly different between the test and reference groups (all P>0.05). The median (interquartile range) testosterone and PSA levels at M12 were 15.50 ng/dl (10.00-31.25 ng/dl) and 0.01 ng/ml (0.01-0.10 ng/ml), respectively, in the test group and 28.00 ng/dl (22.00-37.00 ng/dl) and 0.02 ng/ml (0.01-0.16 ng/ml), respectively, in the reference group. No significant differences were observed in the M1-baseline, M3-baseline, M6-baseline and M12-baseline changes of testosterone or PSA levels between the two groups (all P>0.050). Additionally, the incidence of all adverse events was not significantly different between the two groups (all P>0.050). Overall, Boennuokang® leuprorelin acetate microspheres exhibited a similar efficacy for suppression of testosterone and PSA levels with a comparable safety profile compared with Enantone® leuprorelin acetate microspheres in patients with PCa.

#2533 Real-world challenges associated with the use of systemic glucocorticoids in a US IgAN cohort

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease and up to 50% of patients progress to kidney failure within 10-20 years. Until early 2022, management of IgAN was primarily focused on supportive care. As outlined in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, patients at high risk of progressive chronic kidney disease despite maximal supportive care can be considered for a 6-month course of systemic glucocorticoids (SGC), although important risks of toxicity and contraindications must be considered. There is currently limited real-world evidence describing the impact of the use of SGC on treatment‑emergent toxicity and healthcare resource utilization (HCRU) in patients with IgAN. We report the incidence of adverse events (AEs) commonly associated with SGC, as well as HCRU rates and costs, in a real-world cohort of IgAN patients, comparing new initiators of SGC with patients who have never initiated SGC. Method This non-interventional, retrospective cohort study was conducted in the TriNetX Dataworks - United States of America Network, a database of de-identified, patient-level electronic medical records (EMR) of approximately 100 million patients. The cohort was selected from a total of 19, 687 patients with IgAN, identified using proxy ICD‑10 codes N02.8 (recurrent and persistent hematuria with other morphologic changes) or N04.1 (nephrotic syndrome) between January 1, 2011, and May 4, 2022. Eligible patients were required to have: an incident diagnosis of IgAN with the same diagnosis within 30-180 days; at least 12 months of EMR history available prior to and after initial IgAN diagnosis; not experienced kidney failure prior to or on the initial date of IgAN diagnosis; and not received SGC prior to the date of diagnosis. Data assessed included demographic and clinical characteristics, IgAN-directed medications, AEs, and HCRU. To promote balance between cohorts, new initiators of SGC (dexamethasone, prednisone, prednisolone, methylprednisolone) were matched with patients who did not receive SGC using a propensity score (PS) approach based on their characteristics at diagnosis. To avoid immortal-time bias, the index date was set as the time of SGC initiation in patients in the SGC cohort; for the non-SGC cohort, a pseudo-index date was assigned using the same lag from diagnosis to index date as their 1:1 PS-matched patient in the SGC cohort. Differences in the cumulative incidence of individual AEs were analyzed using the chi-square test or Fisher's exact test, and differences in HCRU rates and costs were analyzed using the Kruskal-Wallis test. Results After implementing the PS approach, the final analysis included 802 patients (401 PS-matched pairs), with a mean age of 41.2 years and 55% being male. Median duration of follow-up was 3.5 and 3.1 years for the SGC and non-SGC cohorts, respectively. Of AEs that occurred in at least ten of the 802 patients, patients who received SGC experienced a significantly increased incidence of all AEs except for fractures, new onset of diabetes, and reported onset of glaucoma (Table 1). Patients who received SGC had a 12-fold increased incidence of severe infections requiring hospitalization compared with the non-SGC cohort. Annualized mean HCRU rates and costs were significantly greater across all HCRU types for patients who received SGC vs those who did not receive SGC, including an 8-fold increase in inpatient visits, a 4-fold increase in emergency department admissions, and twice as many ambulatory visits (Fig. 1). Results were consistent when the cohort was restricted to patients with IgAN identified using only the ICD-10 code N02.8 (recurrent and persistent hematuria with other morphologic changes). Conclusion The findings of this real-world analysis demonstrate significant side effects and costs for IgAN patients treated with SGC compared with patients not treated with SGC, underscoring the recommendation in the 2021 KDIGO guidelines to carefully consider treatment-emergent toxicity before treating IgAN patients with SGC.

Factor XI as a new target for prevention of thromboembolism in cardiovascular disease: a meta-analysis of randomized controlled trials.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

Efficacy and safety of once-weekly basal insulin versus once-daily basal insulin in patients with type 2 diabetes: A systematic review and meta-analysis

Background: Once-weekly insulin is expected to improve treatment compliance and durability and lead to better glycemic control. Several clinical trials on once-weekly insulin have recently been published. We conducted a systematic review and meta-analysis to investigate the efficacy and safety of once-weekly insulin versus once-daily insulin in type 2 diabetes (T2D). Methods: The following databases were searched for studies: PubMed, EMBASE, and Cochrane library (From January 1, 1946 to May 9, 2023). All randomized trials comparing weekly versus daily insulin in T2D were eligible for inclusion. Data analysis was performed using STATA 17.0 software (Stata Corporation, College Station, TX). The main outcomes and indexes included reduction in Hemoglobin A1c (HbA1c), fasting plasma glucose and bodyweight, proportion of patients achieving HbA1c &lt; 7%, time-in-range 70 to 180 mg/dL and adverse events. Results: This systematic review and meta-analysis included 7 randomized controlled studies involving 2391 patients (1347 receiving 1-week insulin and 1044 receiving 1-day insulin). Once-weekly insulin was not inferior to once-daily insulin in HbA1c change [estimated treatment difference (ETD) = −0.05; 95% confidence intervals (CI): −0.14 to 0.04), HbA1c &lt; 7% (odds ratio = 1.14; 95% CI: 0.87–1.50), fasting plasma glucose (ETD = 0.09; 95% CI: −0.19 to 0.36) and body weight loss (ETD = 0.27; 95% CI: −0.36 to 0.91). In terms of time-in-range 70 to 180 mg/dL, weekly insulin was superior to daily insulin (MTD = 3.84; 95% CI: 1.55–6.08). Icodec was associated with higher incidence of all adverse events (odds ratio = 1.20; 95% CI: 1.03–1.48; P = .024), but did not result in high risk of serious and severe adverse events. Moreover, icodec and Basal Insulin Fc did not result in higher incidence of hypoglycemia compared with insulin daily. Conclusion: Our meta-analysis found that insulin weekly was well tolerated and effective for glycemic control. Once-weekly insulin was not inferior to once-daily insulin in both efficacy and safety in T2D.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma

There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. ClinicalTrials.gov Identifier: NCT03581786.

Comparative pharmacokinetics of two formulations of 2.5-mg rivaroxaban in healthy Korean subjects.

Rivaroxaban is a direct factor Xa inhibitor used for the prevention and treatment of thromboembolic disorders. The objective of this study was to compare the pharmacokinetic profiles of two rivaroxaban formulations after a single dose of rivaroxaban (2.5-mg tablet) in healthy Korean subjects. This study was a randomized, open-label, single-dose, two-period, crossover study that included 34 healthy adult subjects under fasting conditions. The test drug (Yuhan rivaroxaban tablet) or reference drug (Xarelto tablet) was administered in each period. Serial blood samples were collected up to 36 hours post-dose. Plasma concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUCt), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) for the ratio of the geometric means of Cmax and AUCt for the test drug/reference drug were calculated to evaluate pharmacokinetic equivalence. A total of 28 subjects were included in the pharmacokinetic analysis. The geometric mean ratios (90% CI) of the test drug/reference drug for rivaroxaban were 1.0140 (0.9794-1.0499) for AUCt and 0.9350 (0.8797-0.9939) for Cmax. All adverse events (AEs) were mild, and there was no significant difference in the incidence of AEs between the formulations. The pharmacokinetic parameters of rivaroxaban were compared between the test and reference drug, and both formulations were bioequivalent. The newly developed rivaroxaban tablet is safe and well tolerated as the reference drug (ClinicalTrials.gov identifiers: NCT05418803).

Comparative Study of Short-Term Efficacy and Safety of Radical Surgery with or without Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer with T4 Stage: A Propensity Score Matching Analysis.

Hyperthermic intraperitoneal chemotherapy (HIPEC) in T4 colorectal cancer (CRC) remains controversial. The study aimed to explore the safety and efficacy of radical surgery (RS) with HIPEC in T4 CRC. Adverse events after HIPEC were estimated by Common Terminology Criteria for Adverse Events version 5.0. The efficacy was evaluated using recurrence-free survival (RFS) and overall survival (OS). Propensity score matching (PSM) was used to reduce the effects of confounders between groups. Of the 417 patients (263 men and 154 women), 165 patients were treated with RS + HIPEC and 252 patients with RS alone. There was no significant difference in the incidence of all adverse events after PSM. Overall RFS and OS were not significantly different at 24 months (p = 0.580 and p = 0.072, respectively). However, in patients with T4b stage CRC (92.1% vs. 77.3%, p = 0.048) and tumor size ≥ 5 cm (93.0% vs. 80.9%, p = 0.029), RFS in the two groups showed a significant difference at 24 months. In summary, the safety of HIPEC in T4 CRC was confirmed. Compared with RS, though RS + HIPEC did not benefit the overall cohort at 24 months, RS + HIPEC could benefit patients with T4b stage CRC and tumor size ≥ 5 cm in RFS.

Comparative Study of Short-Term Efficacy and Safety of Mitomycin versus Lobaplatin for Hyperthermic Intraperitoneal Chemotherapy after Radical Surgery in Colorectal Cancer with High-Risk Factors for Peritoneal Carcinomatosis: A Propensity Score Matching Analysis.

The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial. Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups. Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028). In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

PS-P07-3: EFFICACY AND SAFETY OF NIFEDIPINE GASTROINTESTINAL THERAPEUTIC SYSTEM VERSUS RAMIPRIL IN CHINESE AND EUROPEAN PATIENTS WITH HYPERTENSION

Objective: In a post-hoc analysis of a multinational, randomized trial, we investigated whether the efficacy and safety of nifedipine gastrointestinal therapeutic system (GITS) and ramipril differed between Chinese and European patients with hypertension. Method: Previously treated (2-week washout) and untreated patients with hypertension were randomly assigned to treatment with nifedipine GITS 30 mg or ramipril 10 mg for 12 months, if they had elevated clinic (≧ 140/90 mmHg) and daytime (≧ 135/85 mmHg) ambulatory systolic/diastolic blood pressure (BP) and standard deviation of home (&gt; 7 mmHg) and daytime systolic BP (&gt; 12 mmHg). BP was measured at each of the clinic visits at baseline and during follow-up. Ambulatory and 7-day home BP monitoring were performed at baseline and 10 weeks and 12 months of follow-up. Results: The 67 Chinese and 101 European patients significantly differed in age (50.9 vs. 54.6 years), body mass index (24.5 vs. 27.0 kg/m2), clinic diastolic BP (87.9 vs. 92.5 mmHg), clinic heart rate (75.0 vs. 70.8 beats/minute) and nighttime diastolic BP (79.3 vs. 75.9 mmHg). However, within each ethnicity, patients were comparable between the nifedipine GITS and ramipril groups (P≧ 0.05). In both Chinese and European patients, BP was similarly reduced in the nifedipine GITS and ramipril groups, except that daytime systolic/diastolic BP reductions were 7.4/4.1 mmHg greater in the ramipril than nifedipine GITS group in Chinese (P = 0.02). The safety profile significantly (P for drug*ethnicity interaction ≦ 0.046) differed between the Chinese and European patients for the incidence of all adverse events (lower on nifedipine GITS in Chinese), ankle edema (higher on nifedipine GITS in Europeans) and dry cough (higher on ramipril in Chinese). Conclusion: In the Chinese and European patients with hypertension, nifedipine GITS and ramipril had similar BP lowering efficacy, but different safety profile and tolerability.

Long-Term Safety and Effectiveness of Erenumab in Patients with Migraine: A Systematic Review and Single-Arm Meta-analysis.

Several studies on use of erenumab for migraine treatment have been published over recent years. However, its long-term safety and effectiveness have not been consistently established in the literature yet. We aimed to perform a qualitative and quantitative analysis of the long-term safety and effectiveness of erenumab for the treatment of migraine headaches. Long-term follow-up was defined as ≥1 year. PubMed, Embase and Cochrane Librarywere systematically searched from inception to 14 June 2022 for studies meeting the inclusion criteria. Risk of bias was assessed using the Newcastle-Ottawa Scale. Fourteen studies, comprising 3574 patients, were included. The total follow-up period ranged from 48 to 268 weeks (i.e., 1 year to 5.6 years). Pooled estimate rates for all adverse events (AEs) were 63% (95% CI 46-78); for serious AEs, 3% (95% CI 1-7); and for AEs leading to discontinuation of erenumab, 3% (95% CI 2-5). Reduction in monthly migraine days (MMDs) was -6.98 (95% CI -8.90 to -5.05) and in migraine-specific medication days (MSMDs) was -6.09 (95% CI -9.43 to -2.75). More than half (57%; 95% CI 51-63) and around one-third (35%; 95% CI 28-42) of patients presented with reductions of ≥50% and ≥75% in MMDs, respectively. Headache Impact Test-6 (HIT-6) score was decreased by -9.68 points (95% CI -12.03 to -7.34). Nine studies were considered of poor methodological quality and five of fair quality. Erenumab has a favorable safety profile, with a low incidence of serious AEs, and sustained efficacy over ≥1 year of follow-up in the treatment of migraine.

Impact of heart rate on adverse events in patients with non-valvular atrial fibrillation: Subanalysis of the J-RHYTHM Registry.

Although heart rate (HR) is reportedly associated with major cardiovascular outcomes in the general population, its impact on adverse events in patients with non-valvular atrial fibrillation (NVAF) remains controversial. Thus, we performed post hoc analyses of data from the J-RHYTHM Registry to clarify this in patients with NVAF. Of 7406 outpatients with NVAF from 158 institutions, 6886 (age, 69.8±9.9years; men, 70.8%), in whom both baseline HR and HR-end (at the time closest to an event or at the last visit of follow-up) were measured during the two-year follow-up period or until the occurrence of an event, constituted the study group. The baseline HR and HR-end values were 72.5±13.3bpm and 73.3±13.3bpm, respectively. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 117 (1.7%), 130 (1.9%), 157 (2.3%), and 58 (0.8%) patients, respectively. Baseline HR was not associated with any adverse event, whereas HR-end (per 1-bpm increase) was significantly associated with an increased incidence of all adverse events. Furthermore, the highest quartile of HR-end (≥80bpm) was independently associated with the incidence of major hemorrhage (adjusted odds ratio [OR], 2.90; 95% confidence interval [CI], 1.69-4.96; P<0.001), all-cause death (OR, 3.42; 95% CI, 1.99-5.88; P<0.001), and cardiovascular death (OR, 5.07; 95% CI, 1.49-17.22; P=0.009) compared with the second quartile (64-71bpm), even after adjusting for known confounding factors, HR-controlling drug use, and systolic blood pressure-end. In patients with NVAF, HR-end was significantly associated with adverse events independent of systolic blood pressure-end, whereas baseline HR was not.

Should dexamethasone alone or in combination be the initial steroid for adult ITP: Still a relevant question.

Corticosteroids are used in first-line treatment in newly diagnosed immune thrombocytopenia. The goal of treatment is primarily to decrease autoantibody-mediated platelet clearance. Ideally initial treatment would not just increase the platelet count but also provide a long-term sustained remission. While many clinicians use prednisone (PDN) as their first choice of corticosteroid, others prefer dexamethasone. The controversy is the subject of debates. Short courses of higher-dose corticosteroids were first reported by the Andersen study in 1994. The study posited high-dose dexamethasone as a 'cure' for all ITP patients. Later, studies addressed the number of dexamethasone cycles, indications to repeat cycles and timing between cycles, with varied long-term results. The results with dexamethasone were compared to PDN in some studies: the four-day cycles of dexamethasone work faster in increasing platelet counts and appear to reduce the occurrence of severe adverse events. Therefore, it is probably a better option for patients with low platelet counts and bleeding diathesis; however, curative superiority, the initial reason to administer it, compared to PDN is not well demonstrated. Across the studies, treatment with high-dose dexamethasone seems to be safer, with lower incidence of all adverse events compared to PDN, which might be a reflection of shorter treatment duration and possibly also lower cumulative steroid dose. Dexamethasone in combination with rituximab in first-line treatment produced higher response rates with better long-term results compared to high-dose dexamethasone alone and is a particularly good option in younger women.

The efficiency of convalescent plasma in COVID-19 patients: A systematic review and meta-analysis of randomized controlled clinical trials.

The objective of this study was to assess whether convalescent plasma therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of Pubmed, Web of Science, Embase, Cochrane library and MedRxiv was performed from January 1st, 2020 to April 1st, 2022. We included studies containing patients with COVID-19 and treated with CCP. Data were independently extracted by two reviewers and synthesized with a random-effect analysis model. The primary outcome was 28-d mortality. Secondary outcomes included length of hospital stay, ventilation-free days, 14-d mortality, improvements of symptoms, progression of diseases and requirements of mechanical ventilation. Safety outcomes included the incidence of all adverse events (AEs) and serious adverse events (SAEs). The Cochrane risk-of-bias assessment tool 2.0 was used to assess the potential risk of bias in eligible studies. The heterogeneity of results was assessed by I^2 test and Q statistic test. The possibility of publication bias was assessed by conducting Begg and Egger test. GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used for quality of evidence. This study had been registered on PROSPERO, CRD42021273608. 32 RCTs comprising 21478 patients with Covid-19 were included. Compared to the control group, COVID-19 patients receiving CCP were not associated with significantly reduced 28-d mortality (CCP 20.0% vs control 20.8%; risk ratio 0.94; 95% CI 0.87-1.02; p = 0.16; I² = 8%). For all secondary outcomes, there were no significant differences between CCP group and control group. The incidence of AEs (26.9% vs 19.4%,; risk ratio 1.14; 95% CI 0.99-01.31; p = 0.06; I² = 38%) and SAEs (16.3% vs 13.5%; risk ratio 1.03; 95% CI 0.87-1.20; p = 0.76; I² = 42%) tended to be higher in the CCP group compared to the control group, while the differences did not reach statistical significance. In all, CCP therapy was not related to significantly improved 28-d mortality or symptoms recovery, and should not be viewed as a routine treatment for COVID-19 patients.Trial registration numberCRD42021273608. Registration on February 28, 2022Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, Identifier CRD42022313265.

Impact of Systolic Blood Pressure Time in Target Range on Adverse Events in Patients With Nonvalvular Atrial Fibrillation (from the J-RHYTHM Registry)

Although time in target range (TTR) of systolic blood pressure (BP), an index of consistency of BP control, is reportedly associated with major cardiovascular outcomes, the impact of BP-TTR on adverse events in patients with nonvalvular atrial fibrillation (NVAF) has not been thoroughly investigated. Thus, we performed a post hoc analysis to clarify it in patients with NVAF using data of the J-RHYTHM registry. Of 7,406 outpatients with NVAF, 7,226 (age, 70 ± 10years; men, 71%), in whom BP was measured 4 times or more (15 ± 5 times) during the 2-year follow-up period or until occurrence of an event, constituted the study group. Systolic BP-TTR, with a target range of 110 to 130mm Hg, was calculated by Rosendaal linear interpolation method. Overall systolic BP-TTR was 50 ± 28%. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 110 (1.5%), 121 (1.7%), 168 (2.3%), and 60 patients (0.8%), respectively. Each 1% increase in systolic BP-TTR was significantly associated with a decreased incidence of all adverse events in the unadjusted model; whereas, significant association was observed only for cardiovascular death (adjusted hazard ratio 0.983, 95% confidence interval 0.971 to 0.995, p=0.006) after adjusting for known confounders and systolic BP at the time closest to an event. In contrast, each 1% increase in systolic BP time in subtarget range of &lt;110mm Hg was significantly associated with an increased risk of thromboembolism (hazard ratio 1.014, 95% confidence interval 1.005 to 1.024, p=0.002). In conclusion, systolic BP-TTR and BP time in subtarget range would be useful for risk evaluation of cardiovascular death and thromboembolism, respectively, in patients with NVAF.

Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis.

To assess the impact of cytochrome P450 (CYP) 2C19 polymorphisms on the clinical efficacy and safety of voriconazole. We systematically searched PubMed, EMBASE, CENTRAL, ClinicalTrials.gov, and three Chinese databases from their inception to 18 March 2021 using a predefined search algorithm to identify relevant studies. Studies that reported voriconazole-treated patients and information on CYP2C19 polymorphisms were included. The efficacy outcome was success rate. The safety outcomes included overall adverse events, hepatotoxicity, and neurotoxicity. A total of 20 studies were included. Intermediate metabolizers (IMs) and poor metabolizers (PMs) were associated with increased success rates compared with normal metabolizers (NMs) [risk ratio (RR), 1.18; 95% confidence interval (CI), 1.03-1.34; I2 = 0%; P = 0.02; RR, 1.28; 95% CI, 1.06-1.54; I2 = 0%; P = 0.01]. PMs were at increased risk of overall adverse events in comparison with NMs and IMs (RR, 2.18; 95% CI, 1.35-3.53; I2 = 0%; P = 0.001; RR, 1.80; 95% CI, 1.23-2.64; I2 = 0%; P = 0.003). PMs demonstrated a trend towards an increased incidence of hepatotoxicity when compared with NMs (RR, 1.60; 95% CI, 0.94-2.74; I2 = 27%; P = 0.08), although there was no statistically significant difference. In addition, there was no significant association between CYP2C19 polymorphisms and neurotoxicity. IMs and PMs were at a significant higher success rate in comparison with NMs. PMs were significantly associated with an increased incidence of all adverse events compared with NMs and IMs. Researches are expected to further confirm these findings. Additionally, the relationship between hepatotoxicity and CYP2C19 polymorphisms deserves clinical attention.

Efficacy and safety of second-line regorafenib after sorafenib or lenvatinib first line in patients with unresectable hepatocellular carcinoma: A real-world study.

e16125 Background: To explore the safety, efficacy and long-term prognosis of patients with unresectable hepatocellular carcinoma (HCC) treated with regorafenib after failure of first-line treatment. Methods: This retrospective single center study included 50 unresectable HCC patients who received regorafenib as a second line treatment in our hospital. Based on the difference of first-line targeted drugs, the 50 patients were divided into sorafenib group (n = 22) and lenvatinib group (n = 28). The adverse events, efficacy and long-term prognosis of sorafenib or lenvatinib followed by regorafenib were analyzed. Results: The median age of the 50 patients was 54.5 years. The patients had the following clinical characteristics: ECOG score 0-1, HbsAg positive, cirrhosis, BCLC stage B/C in 95.5%, 95.5%, 90.9% and 90.9% of all patients respectively. The baseline clinical characteristics between the sorafenib and lenvatinib groups were not statistically different (all p &gt; 0.05), except for age and total bilirubin which were in favour of lenvatinib group. Regorafenib was administered oral 160 mg once daily during weeks 1–3 of each 4-week cycle. For 50 HCC patients, the incidence rate of adverse events after accepting regorafenib was 68%. The incidence rate of grade I/II and III/IV adverse events was 60% and 24%, respectively. According to the standards of RECIST 1.1 and mRSCIST, objective response rate (ORR) and disease control rate (DCR) after receiving regorafenib were 14.0%, 62.0% and 22.0%, 60.0%, respectively. There was no significant difference in incidence of all adverse events and grade III/IV adverse events, ORR and DCR between the two groups ( p &gt; 0.05). In terms of long-term prognosis, total overall survival (TOS) and regorafenib overall survival (ROS) in sorafenib group and lenvatinib group were 23.0 months (95% confidence interval [CI]: 15.1-30.9) vs. 29.7 months (95CI: 21.4-38.1), and 11.7 months (95CI: 7.1-16.3) vs. 15.9 months (95CI: 8.3-23.5). The difference was statistically significant ( p= 0.041 and P = 0.045). The regorafenib progression-free survival (RPFS) was 5.6 months (95CI: 1.9-9.2) vs. 8.0 months (95CI: 5.1-10.9) in sorafenib group and lenvatinib group, respectively. The difference was not statistically significant ( P = 0.380). Conclusions: The data suggest that regorafenib is an effective drug for second-line treatment of HCC, with an acceptable toxicity level, an ORR of 14%-22% and a DCR of 62%-60%. Both TOS and ROS in lenvatinib group are better than those in sorafenib group. The possible mechanisms was that EGFR activation limits the response of HCC cells to lenvatinib. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after the disease progresses.

Single low-dose tafenoquine combined with dihydroartemisinin–piperaquine to reduce Plasmodium falciparum transmission in Ouelessebougou, Mali: a phase 2, single-blind, randomised clinical trial

SummaryBackgroundTafenoquine was recently approved as a prophylaxis and radical cure for Plasmodium vivax infection, but its Plasmodium falciparum transmission-blocking efficacy is unclear. We aimed to establish the efficacy and safety of three single low doses of tafenoquine in combination with dihydroartemisinin–piperaquine for reducing gametocyte density and transmission to mosquitoes.MethodsIn this four-arm, single-blind, phase 2, randomised controlled trial, participants were recruited at the Clinical Research Unit of the Malaria Research and Training Centre of the University of Bamako in Mali. Eligible participants were aged 12–50 years, with asymptomatic P falciparum microscopy-detected gametocyte carriage, had a bodyweight of 80 kg or less, and had no clinical signs of malaria defined by fever. Participants were randomly assigned (1:1:1:1) to standard treatment with dihydroartemisinin–piperaquine, or dihydroartemisinin–piperaquine plus a single dose of tafenoquine (in solution) at a final dosage of 0·42 mg/kg, 0·83 mg/kg, or 1·66 mg/kg. Randomisation was done with a computer-generated randomisation list and concealed with sealed, opaque envelopes. Dihydroartemisinin–piperaquine was administered as oral tablets over 3 days (day 0, 1, and 2), as per manufacturer instructions. A single dose of tafenoquine was administered as oral solution on day 0 in parallel with the first dose of dihydroartemisinin–piperaquine. Tafenoquine dosing was based on bodyweight to standardise efficacy and risk variance. The primary endpoint, assessed in the per-protocol population, was median percentage change in mosquito infection rate 7 days after treatment compared with baseline. Safety endpoints included frequency and incidence of adverse events. The final follow-up visit was on Dec 23, 2021; the trial is registered with ClinicalTrials.gov, NCT04609098.FindingsFrom Oct 29 to Nov 25, 2020, 1091 individuals were screened for eligibility, 80 of whom were enrolled and randomly assigned (20 per treatment group). Before treatment, 53 (66%) individuals were infectious to mosquitoes, infecting median 12·50% of mosquitoes (IQR 3·64–35·00). Within-group reduction in mosquito infection rate on day 7 was 79·95% (IQR 57·15–100; p=0·0005 for difference from baseline) following dihydroartemisinin–piperaquine only, 100% (98·36–100; p=0·0005) following dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg, 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg, and 100% (100–100; p=0·0001) following dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg. 55 (69%) of 80 participants had a total of 94 adverse events over the course of the trial; 86 (92%) adverse events were categorised as mild, seven (7%) as moderate, and one (1%) as severe. The most common treatment-related adverse event was mild or moderate headache, which occurred in 15 (19%) participants (dihydroartemisinin–piperaquine n=2; dihydroartemisinin–piperaquine plus tafenoquine 0·42 mg/kg n=6; dihydroartemisinin–piperaquine plus tafenoquine 0·83 mg/kg n=3; and dihydroartemisinin–piperaquine plus tafenoquine 1·66 mg/kg n=4). No serious adverse events occurred. No significant differences in the incidence of all adverse events (p=0·73) or treatment-related adverse events (p=0·62) were observed between treatment groups.InterpretationTafenoquine was well tolerated at all doses and accelerated P falciparum gametocyte clearance. All tafenoquine doses showed improved transmission reduction at day 7 compared with dihydroartemisinin–piperaquine alone. These data support the case for further research on tafenoquine as a transmission-blocking supplement to standard antimalarials.FundingBill & Melinda Gates Foundation.TranslationsFor the French, Portuguese, Spanish and Swahili translations of the abstract see Supplementary Materials section.

Adverse events during intrahospital transport of critically ill patients: A systematic review and meta-analysis.

Intrahospital transport of critically ill patients is often necessary for diagnostic procedures, therapeutic procedures, or admission to the intensive care unit. The aim of this study was to investigate and describe safety and adverse events during intrahospital transport of critically ill patients. A systematic search was performed of MEDLINE and the Cochrane Central Register of Controlled Trials for studies published up to June 3, 2020, and of the International Clinical Trials Platform Search Portal and ClinicalTrials.gov for ongoing trials. We selected prospective and retrospective cohort studies published in English on intrahospital transport of critically ill patients, and then performed a meta-analysis. The primary outcome was the incidence of all adverse events that occurred during intrahospital transport. The secondary outcomes were death due to intrahospital transport or life-threatening adverse events, minor events in vital signs, adverse events related to equipment, durations of ICU and hospital stay, and costs. A total of 12,313 intrahospital transports and 1898 patients from 24 studies were included in the meta-analysis. Among 24 studies that evaluated the primary outcome, the pooled frequency of all adverse events was 26.2% (95% CI: 15.0-39.2) and the heterogeneity among these studies was high (I2=99.5%). The pooled frequency of death due to intrahospital transport and life-threatening adverse events was 0% and 1.47% each, but heterogeneity was also high. Our findings suggest that adverse events can occur during intrahospital transport of critically ill patients, and that the frequency of critical adverse events is relatively low. The results of this meta-analysis could assist in risk-benefit analysis of diagnostic or therapeutic procedures requiring intrahospital transport of critically ill patients. UMIN000040963.

Safety and Effectiveness of Varenicline in Korean Smokers: A Nationwide Post-Marketing Surveillance Study.

PurposeVarenicline has demonstrated its safety and efficacy in Western studies including <3% of Asian participants. This prospective multi-center observational study investigated the safety and effectiveness of varenicline in Korean smokers.Patients and MethodsSmokers prescribed varenicline for the first time were enrolled from 252 medical institutions. Investigators recorded and graded all adverse events (AEs). To assess the effectiveness of varenicline, the 7-day point prevalence (PP) of smoking cessation was evaluated at the four visits during the 12-week treatment course. Rates of AE incidence and smoking cessation were analyzed using Chi-squared test or Fisher’s exact test. This study is registered with ClinicalTrials.gov, number NCT00483002.ResultsA total of 3719 and 3700 study subjects were included in the safety and effectiveness analyses, respectively. Overall, 346 (9.3%) subjects experienced 471 AEs: 358 mild, 97 moderate, 9 severe, and 7 serious. The most frequent AEs were nausea (5.1%), dyspepsia (0.8%), abnormal dreams (0.8%), insomnia (0.8%), and headache (0.7%). Among the subjects with AEs, 73 subjects discontinued treatment, of which 68 were due to AE occurrence. The 7-day PP of smoking cessation at weeks 1–2, 3–6, 7–10, and ≥ week 11 were 51.7% (387/749), 59.6% (1740/2922), 73.3% (1114/1520), and 77.0% (1116/1449), respectively (p for trend = 0.023). Comorbidities and allergies were associated with a higher incidence of AEs and lower smoking cessation rate (p < 0.05). Younger subjects, infrequent alcohol drinkers, and lighter smokers showed a higher smoking cessation rate (p < 0.05).ConclusionVarenicline in adult Korean smokers was well tolerated and effective as a smoking cessation aid in routine clinical practice.