Cumulative Incidence Of Adverse Events Research Articles

Outcomes of Cold Stored Saphenous Vein Allografts for Haemodialysis Vascular Access

The aim of this study was to evaluate the outcome of cold stored saphenous vein allografts (CSVAs) for haemodialysis vascular access. A retrospective, two centre study was conducted between January 2016 and December 2020 of all patients who had CSVA placement for haemodialysis vascular access. Primary, primary assisted, and secondary patency were analysed, as well as procedural complications and re-interventions. A total of 109 patients (n = 55 women) with a mean age of 67.2 ± 13.6 years, with no options for creating an autogenous arteriovenous fistula, were included in the study. At 1 year, primary, primary assisted, and secondary patency were 38%, 59%, and 73%, respectively; and at 2 years they were 20%, 43%, and 55%, respectively. During a mean follow up period of 26 ± 18 months, five patients (4.6%) had an access infection, with no related death. During the follow up period, 32 patients (29.4%) died and 13 patients (11.9%) underwent a kidney transplant. None of these patients showed immunoconversion before transplantation. The cumulative incidence of adverse events by the Fine-Gray method was calculated. Considering competing risks (death and renal transplantation), 9% of patients lost their vascular access at 1 year and 18% at 2 years. Moreover, 57.8% patients had stenosis, mainly on the outflow (45.9%), and 49.5% had thrombosis. With a comparable patency rate associated with a low rate of infection, CSVA offers a potential alternative to expanded polytetrafluoroethylene grafts. This creates haemodialysis vascular access when the venous capital is exhausted in patients with reported risk factors for vascular access infection, i.e., insertion in the thigh, advance age, diabetes mellitus, immunocompromised state, obesity, or revision of an infected prosthetic graft.

P636 Comparison of the real-world efficacy of filgotinib with tofacitinib in patients with refractory ulcerative colitis: A single-center retrospective study

Abstract Background Several Janus kinase inhibitors have recently been launched for the treatment of ulcerative colitis (UC). However, there are few reports comparing the efficacy and safety of each drug in patients with refractory UC, especially with filgotinib (FIL), which was recently launched and can be concomitantly used with thiopurines. We herein aimed to compare the real-world efficacy and safety of tofacitinib (TOF) and FIL in induction therapy for patients with refractory UC. Methods Patients with refractory UC, who received either TOF 20mg/day or FIL 200mg/day from May 2018 to October 2023 in Hyogo Medical University Hospital were included in this study. Primary outcomes were clinical response rates at 2, 4, and 8 weeks after administration of TOF or FIL. Clinical response was defined as a decrease of partial Mayo Score (pMS) of ≥2 from baseline and rectal bleeding subscore is ≤1 or a decrease of ≥1 from baseline. Secondary outcomes were cumulative incidences of adverse events during the observation period. Results Of the 230 refractory patients with UC, 197 received TOF and 33 received FIL treatment. The median age was 37 [IQR 27–49] and 49 [33–54] years, and the median disease duration was 3 [1–10] and 5 [2–10] years, respectively. Median durations of observation were 118 [52–188] weeks in the TOF group and 41 [29–60] weeks in the FIL group, median baseline pMS were 6 [5–7] and 5 [5–6], and serum CRP levels were 3.8 [1.3–12.3] and 1.8 [0.3–3.3] mg/L, respectively. Thirty-eight (19.3%) patients in the TOF group and 3 (9.0%) patients in the FIL group received systemic steroids, and 8 (24.2%) in the FIL group received thiopurine at baseline. The clinical response rates at 2, 4 and 8 weeks were 58.4%, 59.4% and 62.9% in the TOF group, and 42.4%, 57.6% and 48.9% in the FIL group, respectively, and the rate tended to be higher in the TOF group than in the FIL group at 2 weeks (p = 0.092). Of the patients who did not respond at 4 weeks, the TOF group had a significantly higher clinical response rate (31.3%) than the FIL group (0%) at 8 weeks (p = 0.032). Among 124 patients with prior anti-TNF-α antibody failure, 59.6% (65/109) of patients in the TOF group and 46.7% (7/15) in the FIL group achieved comparable clinical responses at 8 weeks (p = 0.407). Fifteen of 197 (7.6%) patients in the TOF group and 2 of 33 (6.1%) in the FIL group did not continue treatment until 8 weeks due to adverse events, but there were no significant differences between the groups. Conclusion Even in patients without a response for up to 4 weeks, TOF treatment may provide a higher clinical response than FIL treatment at 8 weeks.

Observational study of clinical toxicity with different formulations of docetaxel in breast cancer patients

ObjectiveTo analyze the excipients and impurities contained in the various docetaxel products available on the market and find out whether they may be responsible for any of the different adverse events associated with the use of docetaxel in patients with breast cancer receiving adjuvant or neoadjuvant treatment. MethodThis is a prospective, multicenter, longitudinal observational, study carried in 26 hospitals in Madrid, Catalonia, Andalusia, and the Valencia Region. The different docetaxel formulations were characterized in terms of their pH, amount of the active ingredient and impurities. The cumulative incidence of adverse events of any grade was evaluated. Adverse events were stratified by drug type and differences were analyzed by means of a chi-square test. ResultsStatistically significant differences were found between the different docetaxel formulations in the cumulative per-cycle incidence of: dosage change, anemia, hypersensitivity reactions and anaphylaxis, neuropathy, palmoplantar and dermal toxicity, ungual toxicity and facial edema. The formulation with the lowest content of impurities showed better results in terms of change of dosage, visits to the emergency room and incidence of anemia and facial edema. However, it was associated with poorer results regarding hospitalization, febrile neutropenia, motor neuropathy and palmoplantar toxicity. ConclusionsThe results of the study showed differences in the incidence of adverse events of the different docetaxel products available in Spain. Such differences were statistically significant for some of the variables analyzed. The study was not able to determine which of the products offered the best toxicity profile. Nor was it possible to establish a correlation with respect to the composition of excipients or the content of impurities.

Effects of low-dose titration on the tolerability and safety of perampanel

PurposeTo evaluate the effects of low-dose titration on the tolerability and safety of perampanel. MethodsWe retrospectively reviewed the records of 1065 patients who started perampanel therapy and compared the incidence of adverse events after standard titration (Group A: starting dose, 2 mg/day; titration speed, 2 mg/2 weeks or longer) and low-dose titration (Group B: starting dose, < 1 mg/day; titration speed, < 1 mg/2 weeks or longer). ResultsAdverse events were reported in 158 patients (14.8%) within the initial first 90 days of starting perampanel (mean concentration, 331 ng/mL). At 90 days, the cumulative incidence of adverse events was significantly higher in Group A than in Group B (24.5% vs. 16.3%, respectively; log-rank test p < 0.001). A Cox proportional hazards model also showed that low-dose titration decreased the incidence risk of adverse events (adjusted hazard ratio, 0.49; 95% confidence interval, 0.35–0.69). When the groups were stratified by use of enzyme-inducing antiseizure medications (inducers), Group A patients without inducers had a significantly higher cumulative incidence of adverse events than the other three subgroups (26.7%, p < 0.001). In patients taking 2 mg of perampanel, median concentrations in patients with or without inducers were 43 ng/mL and 204 ng/mL, respectively. ConclusionPerampanel is generally initiated at 2 mg, but serum perampanel concentrations show substantial interindividual variation. Our study suggests that care must be taken when setting the starting dose of perampanel. In particular, low-dose titration is recommended in patients not taking inducers.

Long Term Follow-up of an Investigator-Initiated Phase 2 Study of Ruxolitinib in MPN-Associated Splancnic Vein Thrombosis (SVT-RUXO)

Background. Splanchnic vein thrombosis (SVT) is a frequent onset manifestation of an underlying myeloproliferative neoplasm (MPN), or can appear during the disease course. We reported primary results of an investigator-initiated Phase 2 study (SVT-RUXO: Eudract 2012-002253-30) with ruxolitinib (RUX) in 21 patients (pts) with MPN-associated SVT (Pieri L, AJH 2017; 92:187). The treatment proved safe and effective in reducing spleen volume by >35% by NMR at the planned primary analysis at 24 weeks (w) in 29% of the pts, and a >50% spleen length reduction by palpation at any time to 24w was obtained by 62% of the pts. Pts who completed the 24w core study and well tolerated the drug and had evidence of clinically-significant improvement were allowed to enter an extension phase up to w72, then entered a long-term FU (see below for pt disposition). Aim. Herein we present long-term follow up (FU) of the SVT-RUXO study after a median of 104 months, range 6.2-9.8y. Study details. The promoter of the study was the AGIMM group of Italian investigators supported by Assoc Italiana per la Ricerca sul Cancro-AIRC. The drug was provided free by Novartis, that had no role in trial design and data analysis. Safety data were reported as cumulative incidence of adverse events (CTCAE v4.03). Clinical responses were defined according to ELN and IWG-MRT criteria. After primary endpoint at 24w, spleen response was assigned by >50% reduction of spleen length by palpation. Results. Patients disposition. A total of 21 pts (38% PMF, 24% PV, 19% ET, 14% PPV-MF, PET-MF 5%) were enrolled and completed the 24w core study for primary end point. Eighteen pts (86%) were still on study at the 72w extension phase time point, and entered a long-term FU until loss of benefit and/or toxicity, or until shift to commercial RUX. The latter pts were continued to be followed under routine care, and data were collected. One pt died at w252 (sepsis), 1 pt entered another trial after 101 mo and 1 received stem cell transplant after 66 mo for loss of response. As by June 30th 2022, 15 (71%) pts are still receiving ruxo, 7 ongoing in the study and 8 receiving commercial drug. Safety. In the post-72w period, the number of AE ranged 0-20/pt. G3 events were thrombocytopenia (n=2), increase of CPK (n=1). All other events were G<2 and included anemia (56%), thrombocytopenia (44%), leukopenia (39%). Four pts (26%) had G2 H. zoster reactivation. SAE included second cancer (1 pheochromocytoma and 1 prostate adenocarcinoma), and one each pneumonia, pleural effusion, encefalopathy, inguinal ernial repair, abdominal pain, sepsis, INR increase in a pt receiving coumadin. Two pts developed COVID-19, with full resolution and under continued ruxo administration. Efficacy. At latest FU, 11 pts (73%) had a maintained spleen response (defined according to IWG-MRT criteria), the remaining 4 had stable spleen volume, in no pt splenomegaly progressed. No pt had disease-related symptoms. Median Hb was 12.7 g/dL (10.0-14.3), Hct 39.8% (31.3-42.4%), platelet count 136x109/L (46-349), leukocyte count 6.5 x109/L (2.2-43.0), neutrophil count 4.43 x109/L (1.3-38.0). Five pts (33%) were in clinical CR (no spleen/liver, no symptom), 12 pts (80%) had hematologic CR. There was no gastrointestinal or other site bleeding episodes and no thrombotic event. One pt required positioning of a TIP for increased portal hypertension with ascites. Exploratory endpoint. Fourteen of 15 pts were JAK2V617F mutated, and serial measurements of JAK2VAF VAF in granulocytes were available in 10 pts up to latest cutoff date. Mean JAK2V617F at baseline was 51.7% (+21.1) and 36.5% (+34.5) at 8+1y. According to IWG-MRT response criteria, 4 pts achieved partial molecular response (PMR; ie, >50% reduction from baseline), 5 pts were not responders; one pt had a deep molecular response (DMR) from VAF 15% to <2%, stable since 5+y. A spleen response was present in all pts with PMR+DMR, 4 had hematologic response, while the remaining one pt with PMR had 63x109/L platelets with normal Hb and leukocyte count. Conclusions. After a median follow-up of 8.6 years, 71% of pts enrolled in the SVT-RUXO study continue to be on drug with substantial efficacy on symptoms and splenomegaly, and no recurrent thrombosis nor GI bleeding events. There was no novel safety signal. Molecular responses were noted in half of pts with serial measurements of JAK2V617F VAF and were associated with hematologic and clinical improvement.

Safety Surveillance of Mass Praziquantel and Albendazole Co-Administration in School Children from Southern Ethiopia: An Active Cohort Event Monitoring.

Preventive chemotherapy (PC) with praziquantel and albendazole co-administration to all at-risk populations is the global intervention strategy to eliminate schistosomiasis and soil-transmitted helminth (STH) from being public health problems. Due to weak pharmacovigilance systems, safety monitoring during a mass drug administration (MDA) is lacking, especially in sub-Saharan Africa. We conducted large-scale active safety surveillance to identify the incidence, types, severity, and associated risk factors of adverse events (AEs) following praziquantel and albendazole MDA in 5848 school children (5-15 years old). Before MDA, 1484 (25.4%) children were prescreened for S. mansoni and STH infections, of whom 71.8% were infected with at least one parasite; 34.5% (512/1484) had S. mansoni and 853 (57.5%) had an STH infection. After collecting the baseline socio-demographic, clinical, and medical data, including any pre-existing clinical symptoms, participants received single dose praziquantel and albendazole MDA. Treatment-associated AEs were actively monitored on days 1 and 7 of the MDA. The events reported before and after the MDA were cross-checked and verified to identify MDA-associated AEs. The cumulative incidence of experiencing at least one type of MDA-associated AE was 13.3% (95% CI = 12.5-14.2%); 85.5%, 12.4%, and 1.8% of reported AEs were mild, moderate, and severe, respectively. The proportion of experiencing one, two, or ≥ three types of AEs was 57.7%, 34.1%, and 8.2%, respectively. The cumulative incidence of AEs in S. mansoni- and (17.0%) and STH (14.1%)-infected children was significantly higher (p &lt; 0.001, χ2 = 15.0) than in non-infected children (8.4%). Headache, abdominal pain, vomiting, dizziness, and nausea were the most common AEs. Being female, older age, having S. mansoni or STH infection were significant predictors of MDA-associated AEs. In summary, praziquantel and albendazole co-administration is generally safe and tolerable. MDA-associated AEs are mostly mild-to-moderately severe and transient. The finding of few severe AEs and significantly high rates of AEs in helminth-infected children underscores the need to integrate pharmacovigilance in MDA programs, especially in high schistosomiasis and STH endemic areas.

A Phase 3 clinical trial validating the potency and safety of an innovative, extra-long-acting interferon in chronic hepatitis C.

Ropeginterferon alfa-2b is a novel mono-pegylated, extra-long-acting interferon. It is administered infrequently and showed good tolerability and clinical activity for the chronic hepatitis B or C treatment in our previous Phase 2 clinical trials. This study aims to validate the potency and safety of this novel agent in a Phase 3 chronic viral hepatitis setting. Patients with chronic hepatitis C genotype 2 were randomized to receive subcutaneous injections of ropeginterferon alfa-2b biweekly or the conventional pegylated interferon alfa-2b weekly for 24 weeks, combined with ribavirin. The primary endpoint was to assess the safety and antiviral potency of ropeginterferon alfa-2b by the non-inferiority in sustained virologic response at 12 weeks after treatment. A total of 222 patients were enrolled. Ropeginterferon alfa-2b group showed a favorable safety profile. Side effects that were generally associated with prior interferon therapies, including neutropenia, asthenia, fatigue, alopecia, dizziness, decreased appetite, nausea, flu-like symptoms including myalgia, pyrexia, and headache, and administration site reactions, were notably less in the ropeginterferon alfa-2b group. The cumulative incidence of adverse events of special interest was also notably higher in the control group. The primary endpoint was met and ropeginterferon alfa-2b showed a better SVR12 rate of 79.8% than 71.9% of the control group. Ropeginterferon alfa-2b is efficacious and has a favorable safety profile as compared with the conventional pegylated interferon alfa-2b. This study together with previous Phase 2 data validated ropeginterferon alfa-2b to be a new treatment option for chronic hepatitis C genotype 2.

Clinical outcomes among distinct groups of patients with severe tricuspid valve regurgitation

Abstract Introduction Severe tricuspid valve regurgitation (TR) is associated with increased 1-year morbidity and mortality. Characterization by valve etiology (primary, secondary, and lead-associated), a classification borrowed from mitral valve disease, has not been universally shown to correlate with outcomes. Purpose Among a large, racially diverse cohort with newly identified severe TR, we aimed to 1) characterize outcomes of severe TR by etiology, and 2) assess whether unsupervised phenoclustering or supervised outcome-driven prediction trees were more effective in establishing subgroups of TR with differential clinical risk profiles. Methods We retrospectively analyzed outcomes of 5-year all-cause death and a composite of death or heart failure hospitalization (HFH) among adult patients with new severe TR identified by echocardiography between 2007 to 2018 at a large academic tertiary referral center in the United States. Patients were initially categorized by etiology of TR, including primary, secondary, and lead-associated. Second, we separately applied unsupervised hierarchical clustering to identify distinct clusters using demographics, clinical, and echo data at the time of diagnosis. Third, we applied a supervised recursive partitioning algorithm (survival trees) by each outcome to identify distinct TR subgroups. We estimated the cumulative incidence of death and composite death or HFH over 5 years by 1) etiology of TR, 2) distinct clusters, and 3) groups identified by supervised learning (prediction trees). Results Among 2,379 consecutive patients with newly identified severe TR, the median age was 70 years, 61% were female, and 40% were Black. Event rates (95% CI) were 30.9 (29.0 to 32.8) events/100 PY for death and 49.0 (45.9 to 52.2) events/100 PY for composite death or HFH over median follow-up of 1.6 years. Event rates were similarly high across TR etiology groups for both death and composite death or HFH (Figure 1). Multiple methods of unsupervised clustering did not yield distinct clusters by patient demographic and imaging characteristics. After applying supervised survival tree modeling, four phenoclusters with distinct clinical prognoses were separately identified for death and composite death or HFH (Figure 2). Variables identified to partition the cohort to discriminate both death and composite death or HFH were age, albumin, blood urea nitrogen, right ventricular contractility, and right ventricular systolic pressure (all p&amp;lt;0.05). Conclusions Five-year cumulative incidence of adverse events among patients with newly diagnosed severe TR was 69% for death and 80% for composite death or HFH. TR etiology did not stratify prognosis, while supervised survival tree models identified phenoclusters with distinct clinical risk. The identified subgroups of severe TR with differential outcomes offer insights towards enrichment in clinical trials of TR and risk/benefit analysis in patients undergoing TR therapies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Abbott

Visual Acuity and Ophthalmic Outcomes 5 Years After Cataract Surgery Among Children Younger Than 13 Years

Cataract is an important cause of visual impairment in children. Data from a large pediatric cataract surgery registry can provide real-world estimates of visual outcomes and the 5-year cumulative incidence of adverse events. To assess visual acuity (VA), incidence of complications and additional eye operations, and refractive error outcomes 5 years after pediatric lensectomy among children younger than 13 years. This prospective cohort study used data from the Pediatric Eye Disease Investigator Group clinical research registry. From June 2012 to July 2015, 61 eye care practices in the US, Canada, and the UK enrolled children from birth to less than 13 years of age who had undergone lensectomy for any reason during the preceding 45 days. Data were collected from medical record reviews annually thereafter for 5 years until September 28, 2020. Lensectomy with or without implantation of an intraocular lens (IOL). Best-corrected VA and refractive error were measured from 4 to 6 years after the initial lensectomy. Cox proportional hazards regression was used to assess the 5-year incidence of glaucoma or glaucoma suspect and additional eye operations. Factors were evaluated separately for unilateral and bilateral aphakia and pseudophakia. A total of 994 children (1268 eyes) undergoing bilateral or unilateral lensectomy were included (504 [51%] male; median age, 3.6 years; range, 2 weeks to 12.9 years). Five years after the initial lensectomy, the median VA among 701 eyes with available VA data (55%) was 20/63 (range, 20/40 to 20/100) in 182 of 316 bilateral aphakic eyes (58%), 20/32 (range, 20/25 to 20/50) in 209 of 386 bilateral pseudophakic eyes (54%), 20/200 (range, 20/50 to 20/618) in 124 of 202 unilateral aphakic eyes (61%), and 20/65 (range, 20/32 to 20/230) in 186 of 364 unilateral pseudophakic eyes (51%). The 5-year cumulative incidence of glaucoma or glaucoma suspect was 46% (95% CI, 28%-59%) in participants with bilateral aphakia, 7% (95% CI, 1%-12%) in those with bilateral pseudophakia, 25% (95% CI, 15%-34%) in those with unilateral aphakia, and 17% (95% CI, 5%-28%) in those with unilateral pseudophakia. The most common additional eye surgery was clearing the visual axis, with a 5-year cumulative incidence of 13% (95% CI, 8%-17%) in participants with bilateral aphakia, 33% (95% CI, 26%-39%) in those with bilateral pseudophakia, 11% (95% CI, 6%-15%) in those with unilateral aphakia, and 34% (95% CI, 28%-39%) in those with unilateral pseudophakia. The median 5-year change in spherical equivalent refractive error was -8.38 D (IQR, -11.38 D to -2.75 D) among 89 bilateral aphakic eyes, -1.63 D (IQR, -3.13 D to -0.25 D) among 130 bilateral pseudophakic eyes, -10.75 D (IQR, -20.50 D to -4.50 D) among 43 unilateral aphakic eyes, and -1.94 D (IQR, -3.25 D to -0.69 D) among 112 unilateral pseudophakic eyes. In this cohort study, development of glaucoma or glaucoma suspect was common in children 5 years after lensectomy. Myopic shift was modest during the 5 years after placement of an intraocular lens, which should be factored into implant power selection. These results support frequent monitoring after pediatric cataract surgery to detect glaucoma, visual axis obscuration causing reduced vision, and refractive error.

Tocilizumab for faster and safer remission of Takayasu's arteritis.

Takayasu's arteritis (TAK) is a large-vessel vasculitis. Glucocorticoids (GCs) combined with cyclophosphamide (CTX) is a common treatment option, but their efficacy is limited. The aim of this retrospective study was to study the efficacy and safety of tocilizumab (TCZ) in the treatment of TAK. A total of 63 patients with TAK were divided into two groups according to different treatment strategies: 31 patients in the TCZ group and 32 patients in the CTX group. After 6 months of treatment, disease activity and side effects were evaluated and were compared between the two groups. After 3 months of treatment, the National Institutes of Health (NIH) score (p = 0.005), Indian Takayasu Clinical Activity Score (ITAS) 2010 (p = 0.043), and the Indian Takayasu Activity Score with the Acute-Phase Response (ITAS.A; p = 0.036) were lower in patients treated with TCZ compared with those treated with CTX. In the TCZ group, the proportion of patients with NIH scores ⩽1 reached 50% after 1 month, 90% after 3 months, and 96% after 6 months of treatment, whereas in the CTX group, these proportion were 36%, 30%, and 78%, respectively. Thus, TCZ treatment of TAK is accompanied with a faster remission rate than CTX treatment. Moreover, the total cumulative incidence of adverse events was lower in the TCZ group than in the CTX group (p = 0.035). TCZ was faster and safer in alleviating TAK.

Time trends of drug-specific actionable adverse events among patients on androgen receptor antagonists: Implications for remote monitoring.

In light of COVID-19, reducing patient exposure via remote monitoring is desirable. Patients prescribed abiraterone/ enzalutamide are scheduled for monthly in-person appointments to screen for adverse events (AEs). We determined time trends of drug-specific actionable AEs among users of abiraterone/enzalutamide to assess the safety of remote monitoring. A chart review was conducted on 828 prostate cancer patients prescribed abiraterone and/or enzalutamide. Data were collected to determine time to actionable first AEs, including hypertension, elevated liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT]), hyperbilirubinemia, and hypokalemia. Survival analysis was used to determine time to AEs. In this study, 425 and 403 patients received enzalutamide and abiraterone, respectively. In total, 25.6% of those who took enzalutamide experienced an AE, compared to 28.8% of patients on abiraterone. For patients using abiraterone and experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were: 67.2%, 81.9%, 90.5%, and 93.9%, respectively. Among enzalutamide users experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were 51.4%, 70.7%, 82.6%, and 88.1%, respectively. The AEs associated with enzalutamide were hypertension and liver dysfunction (77.1% and 22.9%, respectively). In the abiraterone group, associated AEs were liver dysfunction (47.4%), hypertension (47.4%), and hypokalemia (5.2%). Attaining AEs secondary to abiraterone/enzalutamide decreases over time and tends to occur within the first six months of therapy. Most actionable AEs can be remotely monitored. Given COVID-19, remote monitoring after six months of initiating abiraterone or enzalutamide appears appropriate.

Abstract MP59: Effects Of Sodium Reduction And Weight Loss On Lightheadedness And Falls In Older Adults: Results From TONE

Background: The Trial of Nonpharmacologic Interventions in the Elderly (TONE) demonstrated the efficacy of sodium reduction and weight loss to reduce hypertension medication use in older adults. However, adverse events related to lightheadedness and falls have not been reported. Objective: To determine whether sodium reduction and weight loss are associated with greater risk of lightheadedness and falls among older adults. Methods: TONE was a randomized trial of 60-80 year-old adults with systolic BP (SBP) and diastolic BP (DBP) below 145 and 85 mm Hg, respectively, while receiving treatment with a single antihypertensive medication. Participants were randomized to behavioral interventions focused on sodium reduction, weight loss, both, or neither (usual care); 3 months after randomization, the antihypertensive medication was withdrawn and only restored later during the study if needed for uncontrolled hypertension. Total follow-up was 36 months post-randomization. Two physicians independently adjudicated adverse event logs, masked to intervention assignment. The primary outcome was a composite of the first occurrence of adverse event related to falls (total N=95): 72 involved orthostatic symptoms (lightheadedness, dizziness, vertigo), while 23 involved hard events (fall or syncope). Hazard ratios were determined via Cox proportional hazards models. Results: Among the 975 participants (mean age 66 yrs, 48% women, 24% black), mean SBP and DBP were 128 and 71 mm Hg. The cumulative incidence of adverse events at 30 months was 0.08, 0.13, 0.11, and 0.14 for usual care, reduced sodium, weight loss, or both, respectively ( Figure ). In adjusted multi-variable analyses, sodium reduction was associated with higher risk of an adverse event (HR 1.52; 95% CI: 1.02, 2.27), while weight loss was not associated with adverse events (HR 1.18; 0.77, 1.79). Conclusions: In the context of antihypertensive medication withdrawal, sodium reduction was associated with a higher risk of fall-related adverse events, predominantly symptoms.

Oral Anticoagulation and Adverse Outcomes after Ischemic Stroke in Heart Failure Patients without Atrial Fibrillation

BackgroundThe safety and effectiveness of oral anticoagulation (OAC) after an ischemic stroke in older patients with heart failure (HF) without atrial fibrillation remains uncertain. MethodsUtilizing Get With The Guidelines Stroke national clinical registry data linked to Medicare claims from 2009-2014, we assessed the outcomes of eligible patients with a history of HF who were initiated on OAC during a hospitalization for an acute ischemic stroke. The cumulative incidences of adverse events were calculated using Kaplan-Meier curves and adjusted Cox proportional hazard ratios were compared between patients discharged on or off OAC. ResultsA total of 8,261 patients from 1,370 sites were discharged alive after an acute ischemic stroke and met eligibility criteria. Of those, 747 (9.0%) were initiated on OAC. Patients on OAC were younger (77.2±8.0 vs. 80.5±8.9 years, p<0.01). After adjustment for clinical covariates, the likelihood of 1 year mortality was higher in those on OAC (aHR: 1.22, 95% CI 1.05-1.41, p<0.01), while no significant differences were noted for ICH (aHR: 1.34, 95% CI 0.69-2.59, p=0.38) and recurrent ischemic stroke (aHR: 0.78, 95% CI 0.54-1.15, p = 0.21). The likelihood of all-cause bleeding (aHR: 1.59, 95% CI 1.29-1.96, p<0.01) and all-cause re-hospitalization (aHR: 1.14, 95% CI 1.02-1.27, p = 0.02) was higher for those on OAC. ConclusionInitiation of OAC after an ischemic stroke in older patients with HF in the absence of atrial fibrillation is associated with death, bleeding and re-hospitalization without an associated reduction in recurrent ischemic stroke. If validated, these findings raise caution for prescribing OAC to such patients.

Safety and Tolerability of Mass Diethylcarbamazine and Albendazole Administration for the Elimination of Lymphatic Filariasis in Kenya: An Active Surveillance Study

Preventive chemotherapy with diethylcarbamazine citrate (DEC) and albendazole (ALB) is the core intervention strategy to eliminate lymphatic filariasis (LF). We conducted a large-scale prospective active safety surveillance study to identify the incidence, type, severity, and risk factors for adverse events (AEs) following mass drug administration (MDA) of single-dose DEC and ALB in 10,010 participants from Kilifi County, Kenya. AEs were actively monitored and graded at 24 h, 48 h, and on day 7 Post-MDA. Out of 10,010 enrolled study participants, 1621 participants reported a total of 3102 AEs during a seven-day follow-up. The cumulative incidence of AEs was 16.2% (95% CI, 15.5–16.9%). The proportion of participants who experienced one, two, or ≥three types of AEs was 9.2%, 4.6%, 2.4%, respectively. AEs were mild (87.3%), moderate (12.4%), and severe (0.3%) and resolved within 72 h. The five most common AEs were dizziness (5.9%), headache (5.6%), loss of appetite (3.3%), fever (2.9%), and drowsiness (2.6%). Older age, taking concurrent medications, ≥three tablets of DEC, and type of meal taken before MDA were significant predictors of AEs. One in six participants experienced systemic mild-to-moderate severity grading and transient AEs. DEC and ALB co-administration for the elimination of LF is generally safe and well-tolerated.

Time trends of drug specific adverse events among patients on androgen receptor antagonists: Implications for remote monitoring.

40 Background: In light of the global pandemic, reducing patient exposure via remote monitoring is desirable. Currently, advanced prostate cancer patients prescribed Abiraterone or Enzalutamide are scheduled for an in-person appointment monthly, to screen for adverse events (AEs). We set out to determine time trends of drug specific AEs in order to determine whether reducing in-person visits for patients taking either Abiraterone or Enzalutamide is feasible. Methods: This chart review was conducted on 667 unique advanced prostate cancer patients, being either metastatic hormone sensitive or castration resistant and utilizing Abiraterone or Enzalutamide. Patients who switched courses of treatment and received both drugs were included twice in the data, resulting in 828 “subjects” overall. Data were collected via accessing electronic patient records, to determine the first sign of an AE related to either Abiraterone or Enzalutamide. These AEs include; hypertension, elevated liver enzymes (bilirubin, AST, ALT) or hypokalemia. Survival analysis was used to determine the time to adverse event. All grade AEs are included in this analysis. Results: In this study, 425 and 403 patients received Enzalutamide and Abiraterone, respectively. In total, 36.3% of those who took Enzalutamide experienced an AE, compared to 43.4% of patients on Abiraterone. For patients utilizing Abiraterone, cumulative incidence of AEs at 3,6,9 and 12 months were: 65.0%, 81.2%, 90.9% and 93.9%, respectively. Among Enzalutamide users, cumulative incidence of AEs at 3,6,9 and 12 months were: 46.8%, 67.5%, 81.2% and 88.3%, respectively. The primary first AEs associated with Enzalutamide consumption were hypertension and liver dysfunction (77.48% and 22.52%). In the Abiraterone group, the first associated AEs were liver dysfunction (48.78%), hypertension (46.34%), and hypokalemia (4.88%). Conclusions: These data suggest that the likelihood of attaining AEs associated with Abiraterone or Enzalutamide utilization decreases over time and tend to occur within the first 6 months of therapy. Furthermore, the vast majority of these AEs can be remotely monitored via outside laboratories and remote blood pressure monitoring. In light of the COVID-19 crisis, remote monitoring after 6 months of taking Abiraterone or Enzalutamide would appear appropriate. Efforts to further safely reduce in person visits should be explored.

Treatment of faecal incontinence with autologous expanded mesenchymal stem cells: results of a pilot study.

Management of faecal incontinence (FI) remains challenging because no definitive optimal treatment for this condition has yet been determined. Regenerative medicine could be an attractive therapeutic alternative for treating FI. Here, we aimed to determine the safety and feasibility of autologous expanded mesenchymal stem cells derived from adipose tissue (AdMSCs) in the treatment of patients diagnosed with structural FI. This was a randomized, multicentre, triple-blinded, placebo-controlled pilot study conducted at four sites in Spain with 16 adults with FI and a sphincter defect. Autologous AdMSCs were obtained from patients from surgically excised adipose tissue. These patients were intralesionally infused with a single dose of 4×107 AdMSCs or a placebo while under anaesthesia. We assessed the safety and feasibility of the treatment as the cumulative incidence of adverse events and the treatment efficacy using the Cleveland Clinic Faecal Incontinence Score, Faecal Incontinence Quality of Life score and Starck criteria to classify sphincter defects and anorectal physiology outcomes. Adipose tissue extraction, cell isolation and intralesional infusion procedures were successful in all the patients. There was only one adverse event connected to adipose tissue extraction (a haematoma), and none was associated with the injection procedure. There were no significant differences in any of the assessed clinical, manometric or ultrasonographic parameters. This study indicates that this infusion procedure in the anal sphincter is feasible and safe. However, it failed to demonstrate efficacy to treat patients with structural FI.

Cardiac radiation dose predicts survival in esophageal squamous cell carcinoma treated by definitive concurrent chemotherapy and intensity modulated radiotherapy

BackgroundThe prognostic significance of cardiac radiation dose in esophageal cancer after definitive concurrent chemoradiotherapy (CCRT) remains largely unknown. We aimed to investigate the association between cardiac dose-volume parameters and overall survival (OS) in esophageal squamous cell carcinoma (ESCC) after definitive CCRT.MethodsOne hundred and twenty-one ESCC patients undergoing definitive CCRT with intensity modulated radiotherapy technique between 2008 and 2018 were reviewed. Cardiac dose-volume parameters were calculated. Survival of patients and cumulative incidence of adverse events were estimated by the Kaplan–Meier method and compared between groups by the log-rank test. The prognostic significance of cardiac dose-volume parameters was determined with multivariate Cox proportional hazards regression analysis.ResultsMedian follow-up was 16.2 months (range, 4.3–109.3). Median OS was 18.4 months. Heart V5, V10, and V20 were independent prognostic factors of OS. Median OS was longer for patients with heart V5 ≤ 94.3% (24.7 vs. 16.3 months, p = 0.0025), heart V10 ≤ 86.4% (24.8 vs. 16.9 months, p = 0.0041), and heart V20 ≤ 76.9% (20.0 vs. 17.2 months, p = 0.047). Lower cumulative incidence of symptomatic cardiac adverse events was observed among patients with heart V5 ≤ 94.3% (p = 0.017), heart V10 ≤ 86.4% (p = 0.02), and heart V20 ≤ 76.9% (p = 0.0057). Patients without symptomatic cardiac adverse events had a higher 3-year OS rate (33.8% vs. 0%, p = 0.03).ConclusionsCardiac radiation dose inversely correlated with survival in ESCC after definitive CCRT. Radiation dose to the heart should be minimized.

No advantage of Imatinib in combination with hydroxyurea over Imatinib monotherapy: a study of the East German Study Group (OSHO) and the German CML study group

Introduction The combination of Imatinib (IM) and hydroxyurea (HU) was explored for the treatment of chronic myelogenous leukemia (CML). Method After in vitro testing and a phase I study (n = 20), 59 patients were randomized in the IM/HU and 29 in the IM arm. According to protocol, 49 propensity-score matched IM patients were included from the CML-IV study. Results Additive specific inhibition of CML cells by IM/HU was detected in vitro. HU 500 mg qd in combination with IM 400 mg qd proved feasible in the phase I study. Overall, no significant difference with respect to major molecular response (MMR) at 18 months (IM/HU and IM 66%; primary endpoint) was observed. Significant differences were noted for MMR at 6 months (p = 0.04) and for cumulative incidences of adverse events (p = 0.03) in favor of IM monotherapy (secondary endpoints). Conclusion IM/HU combination was more potent in selectively inhibiting CML cells in vitro, but not superior to IM in vivo. (NCT02480608)

Safety and efficacy of complete versus near-complete coiling in treatment of intracranial aneurysms

ObjectiveThis study aimed to evaluate the clinical and angiographic outcomes of aneurysms that were completely or near-completely embolized and ascertain whether complete embolization is important in the stent-assisted coiling (SAC) of intracranial aneurysms. MethodsThis retrospective study enrolled 390 patients (417 aneurysms). Among them, complete (100%) or near-complete (>90%) angiographic obliteration of the aneurysms on immediate angiography was accomplished. Baseline characteristics, complications, angiography follow-up results, and clinical outcomes were analyzed. ResultsCumulative adverse events occurred in 30 patients (7.7%), including thromboembolic complications in 17 (4.4%), intraoperative rupture in 10 (2.6%), and others in 3 (0.8%). Statistical analyses revealed an increased intraprocedural rupture rate in the initial completely occluded aneurysms (5.6% compared with 1.0%). The incidence of cumulative adverse events was higher in patients with completely occluded aneurysms (11.1%) than in those with near-completely occluded aneurysms (5.5%). Angiography follow-up was available for 173 aneurysms. Aneurysm occlusion status at follow-up was correlated with stent placement (p ​= ​0.000, odds ratio ​= ​5.847), size (p ​= ​0.000, odds ratio ​= ​6.446 for tiny aneurysms; and p ​= ​0.001, odds ratio ​= ​5.616 for small aneurysms), and initial aneurysm occlusion status (p ​= ​0.001, odds ratio ​= ​3.436). Complete occlusion at follow-up was seen in 82.6% of the initial complete occlusion group versus 63.0% of the initial near-complete occlusion group. The incidence of complete occlusion at follow-up was higher in the initial completely occluded aneurysms with SAC (100%) than in the initial completely occluded aneurysms with non-SAC (65.2%). ConclusionsInitial complete treatment may lead to higher complication rates and good clinical outcomes at follow-up. Stent placement may enhance progressive aneurysm occlusion. Initial complete occlusion with SAC can provide durable closure at follow-up.

Final Analysis at 5 Years Follow up of Patients with MPN-Associated Splanchnic Vein Thrombosis Treated with Ruxolitinib in a Phase 2 Study

Background: A myeloproliferative neoplasm (MPN) is frequent underlying cause of splanchnic vein thrombosis (SVT). We reported that ruxolitinib, a JAK1/2 inhibitor, was safe in patients (pts) with MPN-associated SVT and effective in reducing spleen size at the planned primary analysis at 24 weeks (w) in an investigator-initiated phase II clinical trial (Pieri L, AJH 2016). Herein we present final long term follow up (FU) data. Methods. A total of 21 MPN-SVT entered the trial in 2012. Pts who completed the 24w core study and well tolerated the drug and had evidence of clinically-significant improvement were allowed to enter an extension phase up to w72, then entered a long term FU. The drug was provided by Novartis, that had no role in trial design nor in data analysis. Safety data were reported as cumulative incidence of adverse events (CTCAE v4.03). Clinical responses were defined according to ELN and IWG-MRT criteria. Results. Patients disposition. Eighteen patients were alive at last follow-up at a median of 5.5y, range 3.7-6.5y. Two pts died before w72 (hepatocarcinoma; unknown cause), 1 pt died at w252 (sepsis). Diagnosis of the 18 pts was: PMF 8 (44%), PV 5 (28%), ET 4 (22%), PET-MF 1 (6%). The DIPSS risk score of the 8 pts with PMF was low in 4 and intermediate-1 in 4. At last FU, 14 patients are still on ruxolitinib (78%), 10 pts still on clinical trial, 4 pts shifted to commercial drug. Four pts (22%) withdrawn treatment after w72 because of inefficacy, withdrawal of consent, unknown reasons, shift to observation only (1 each). Safety. Thirteen pts (72.2%) had adverse events; the median number of events per patient was 5 (range, 0-37). Five pts had G2 thrombocytopenia plus 1 pt G3 (28%), 9 had G2 anemia (50%), 1 had G2 neutropenia (6%). There were 4 non-hematologic G3 adverse events (22%), one drug-related (CPK increase) that resolved with dose reduction. Six pts developed G1-2 infections (33%), 4 had Herpes Zoster reactivation (22%), 1 developed second cancer (pheochromocytoma at w96; 6%). Efficacy. Spleen response (defined as percentage reduction of spleen length from left costal margin (LCM) from baseline value as by IWG-MRT criteria) was available in 16 of 18 pts on treatment. Of 8 pts who obtained spleen response at w72, 4 pts had a complete response, while the remaining 4 pts had a spleen reduction &gt;50%. At last FU, 6 of 8 pts (75%) adjudicated as spleen responders at w72 maintained the response. None of the 8 pts who had not obtained a spleen response at w72 acquired it at the last FU. According to ELN/IWG-MRT criteria of disease response, 7 pts had partial response, 11 had stable disease. At abdominal vessel eco scan, thrombosis improved in 3 of 12 evaluated pts (25%) and remained stable in the remaining 9. Of the 16 pts with endoscopic evaluation at last FU, complete resolution of oesophageal varices was documented in 3/12 with baseline varices (25%), worsening in 4 (33%), stable in 5 (42%), while no de-novo formation of F1 varices was documented in the remaining 4 (33%). No pt had gastrointestinal bleeding episodes. Exploratory endpoints. Included changes in the level of JAK2V617F variant allele burden (VAF) at last FU, available in 13 of 15 JAK2V617F mutated pts. VAF remained stable in 2 pts (13%), increased by 34% (range 25-40) in 3 pts, while 8 pts (62%) had a reduction &gt;10% (range 18-96), of whom 6 (46%) had a reduction &gt;50% (median 82%, range 70-96). By correlative analysis of JAK2 VAF changes and spleen response, 3 of 6 pts with VAF reduction of &gt;50% had complete spleen response, as compared to none of the 3 pts who had an increase of VAF. Conclusions. After a median follow-up of 5.5 years, ruxolitinib continues to be safe in pts with MPN-associated SVT and maintains efficacy against splenomegaly in 33% of the pts. Of note, the large majority of pts (67%) showed stabilization or improvement of oesophageal varices, supporting the hypothesis that sustained reduction of enlarged spleen might contribute to decrease the upstream venous system pressure. Significant reduction of JAK2V617F VAF&gt;50% was documented in 40% of the pts, although it was not clearly correlated with clinical improvement. Disclosures Rumi: novartis: Honoraria, Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Ruxolitinib use in essential thrombocythemia