The effectiveness of split tablet dosing versus alternate-day dosing of warfarin: a randomized control trial

Due to large dosage variation, a variety of warfarin prescription regimens are utilized for specific doses such as tablet splitting, or pill strength alternating. The clinical comparison between the two is lacking. We hypothesize that both approaches result in different times in therapeutic range. We randomized patients with specific warfarin dosage and stable INR for 6 months or longer to receive the whole tablet, alternate-day dosing or the split tablet, same daily-dosing regimen without initial dose change and followed them every 6 weeks for 6 months. The primary outcome was a time in therapeutic range of 2.0–3.0. The secondary outcomes included dosage, compliance, INR, anticoagulant-related events. A total of 66 patients were enrolled, 32 randomly assigned to the split tablet regimen (group S) and 34 to the alternate-day regimen (group A) with two withdrawers. The mean age was 58.6 ± 8.5 years. All baseline characteristics of both groups were similar. The average time in therapeutic range was 72.8 ± 25.4% in group S and 74.9 ± 22.0% in group A (p = 0.72). There were no significant differences in warfarin dosage, compliance, INR and, complications between the two groups. Both warfarin prescription methods, the split tablet and the alternate-day had comparable time in the therapeutic range.

Tacrolimus trough levels in kidney transplant recipients

Background It is very important that kidney transplant recipients (KTRs) take immunosuppressive drugs to prevent graft rejection. This study aimed to identify the tacrolimus trough levels (TTL)-mean, TTL-standard deviation (SD), and TTL- coefficient of variation (CV) as well as factors affecting these values over a 2-year period in clinically stable patients > 5 years after kidney transplantation (KT). Methods This retrospective study analyzed data from 248 adult outpatients > 5 years after KT. Medical chart data, including TTL, graft rejection, and tacrolimus dose change during a 2-year period, between January 2017 and December 2018, were collected. Multivariable regression analyses were conducted to determine the factors influencing the TTL-mean, TTL-SD, and TTL-CV. Results The TTL-mean, TTL-SD, and TTL-CV were 6.00 ± 1.07 ng/mL, 1.51 ± 1.09 ng/mL, and 0.25 ± 0.14, respectively. The TTL-mean, TTL-SD, and TTL-CV did not differ according to sex, type of donor, retransplant, pretransplant kidney disease, body mass index, or posttransplant time; hence, they are stable in kidney transplant recipients > 5 years after KT. The higher the TTL-mean, the higher the TTL-SD. Age and the TTL-SD significantly predicted the TTL-mean (p < .001). Tacrolimus dose change and the TTL-mean significantly predicted the TTL-SD (p < .001). Tacrolimus dose change significantly predicted the TTL-CV (p = .008). Conclusion In clinically stable KTRs, TTL-SD and TTL-CV change sensitively in relation to tacrolimus dose changes. Therefore, changes in TTL-SD and TTL-CV in stable KTRs with no tacrolimus dose change require medical interest and attention.

The Effectiveness of Split Tablet Dosing Versus Alternate-Day Dosing of Warfarin: A Randomized Control Trial

Due to large dosage variation, a variety of warfarin prescription regimens are utilized for specific doses such as tablet splitting, or pill strength alternating. The clinical comparison between the two is lacking. We hypothesize that both approaches result in different times in therapeutic range. We randomized patients with specific warfarin dosage and stable INR for 6 months or longer to receive the whole tablet, alternate-day dosing or the split tablet, same daily-dosing regimen without initial dose change and followed them every 6 weeks for 6 months. The primary outcome was a time in therapeutic range of 2.0 to 3.0. The secondary outcomes included dosage, compliance, INR, anticoagulant-related events. A total of 66 patients were enrolled, 32 randomly assigned to the split tablet regimen (group S) and 34 to the alternate-day regimen (group A) with two withdrawals. The mean age was 58.6 ± 8.5 years. All baseline characteristics of both groups were similar. The average time in therapeutic range was 72.8 ± 25.4% in group S and 74.9 ± 22.0% in group A (p = 0.72). There were no significant differences in warfarin dosage, compliance, INR and, complications between the two groups. Both warfarin prescription methods, the split tablet and the alternate-day had comparable time in the therapeutic range.

Real-world Utilisation of the Rivastigmine Transdermal Patches Accompanying the use of Risk Minimisation Tools in Patients with Dementia

Background: Transdermal patches are convenient to use, especially in patients with Alzheimer’s disease (AD)-associated dementia. However, various identified risks of errors in ad- ministering the patches cannot be disregarded. Patient Reminder Cards (PRCs, included a Medica- tion record sheet [MRS]) have been recently introduced as a risk minimisation tool to prevent incor- rect patch use (IU). Objectives: This study aimed to assess the effectiveness of PRCs to prevent IU and to investigate the dose titration pattern of rivastigmine patches in a real-world setting. Methods: This multinational, observational, 11-month study included patients with AD currently using rivastigmine patches (4.6 mg/day, 9.5 mg/day, 13.3 mg/day) accompanied by a caregiver. Study outcomes were IU, including multiple patch use (MPU), incorrect patch placement, other IUs, perceived usefulness of the PRCs, and titration patterns of the patches. Results: Of the total 614 patients included, most were aged ≥65 years and had mild-to-moderate AD. Before and during the study, 27.7% and 18.0% of patients reported IU, respectively. Most pa- tients used MRS, and 73.5% rated it ‘helpful’ and reported lower rates of IU than those who report- ed it ‘not helpful’ (13.9%–16.5% vs. 20.2%). Overall, 141 patients had dose titrations, with 75.8% being up-titrated from 4.6 mg/day to 9.5 mg/day after a mean duration of 58 days. Safety findings were consistent with the established profile for the rivastigmine patch. Conclusion: PRC was effective as a risk minimisation tool in limiting the inappropriate use of ri- vastigmine patches. The majority of patients requiring dose-change were up-titrated to 9.5 mg/day patches.

337 A Multicenter Open-label Pilot Study Evaluating Next-Dose Transition From Zolpidem to Lemborexant: Analysis of Female Subgroup

Introduction Dosing paradigms for transitioning patients to lemborexant (LEM) from zolpidem (ZOL: immediate [IR] or extended-release [ER]) were examined in E2006-A001-312 (Study 312; NCT04009577), an open-label pilot study. Given insomnia prevalence in women, post hoc analyses in female subjects were conducted. Methods Study 312 included: 3-week Screening Period (subjects continued ZOL); 2-week Titration Period (TITR); 12-week Extension Period (EXT); 4-week Follow-up. Adults with insomnia taking ZOL-IR or ZOL-ER intermittently (3–4 nights/week) or frequently (≥5 nights/week) were enrolled. Subjects with intermittent, or one week each of intermittent and frequent ZOL use, were assigned to Cohort-1 and started TITR with LEM 5mg (LEM5). Frequent ZOL users (Cohort-2) were randomized 1:1 to LEM5 (Cohort-2A) or LEM 10mg (LEM10; Cohort-2B). Subjects who transitioned to LEM could opt into EXT. Subjects could change LEM dose during TITR (only once) and during EXT. The primary endpoint was the proportion of subjects who transitioned to LEM at end of TITR. Treatment-emergent adverse events (TEAEs) were assessed by dose at time of TEAE. Results Overall, 35 subjects were female and 29/35 (82.9%) transitioned to LEM. In Cohort-1, 7 subjects began TITR; all transitioned to LEM (5 subjects ended TITR on LEM5; 2 ended on LEM10). In Cohort-2A, 14 subjects began TITR with LEM5; 12/14 (85.7%) transitioned (6 subjects each ended TITR on LEM5 or LEM10). In Cohort-2B, 14 subjects began TITR with LEM10; 10/14 (71.4%) transitioned to LEM (3 subjects ended TITR on LEM5 and 7 on LEM10). All 29 transitioned subjects opted into EXT, and 27/29 (93.1%) completed the study. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change during EXT was 14.5 and 17.0 days for LEM5 and LEM10, respectively. Overall, most TEAEs were mild/moderate in severity. Across TITR and EXT, more TEAEs occurred with LEM10 than with LEM5; the most common TEAEs were somnolence (n=3) and abnormal dreams (n=3). Conclusion Most female subjects successfully transitioned from intermittent or frequent ZOL-IR/ZOL-ER use to LEM and completed the study. LEM was generally well tolerated. The safety profile was consistent with that observed in Phase 3 studies. Support (if any) Eisai Inc.

335 Evaluation of Dose Transition From Zolpidem to Lemborexant Across 14 Weeks: Results From a Multicenter Open-label Pilot Study

Introduction E2006-A001-312 (Study 312; NCT04009577) was an open-label pilot study that examined pre-specified dosing paradigms for transitioning patients from zolpidem (ZOL: immediate [IR] or extended-release [ER]) to the dual orexin receptor antagonist lemborexant (LEM; 5mg [LEM5] or 10mg [LEM10]). Methods Study 312 included a 3-week Screening Period (subjects continued ZOL), 2-week Titration Period (TITR), 12-week Extension Period (EXT), and 4-week Follow-up Period. Adults with insomnia who were intermittent (3–4 nights/week) or frequent (≥5 nights/week) ZOL-IR or ZOL-ER users participated. Intermittent ZOL users and subjects with one week each of intermittent and frequent ZOL usage were assigned to Cohort-1 and began TITR with LEM5. Frequent ZOL users were assigned to Cohort-2 and randomized 1:1 to LEM5 or LEM10. Subjects who successfully transitioned to LEM had the option to enter EXT. During TITR and EXT, subjects could change LEM dose (only once during TITR). The primary endpoint was the proportion of subjects who transitioned to LEM at the end of TITR. Treatment-emergent adverse events (TEAEs) were assessed based on dose at time of TEAE. Results Fifty-three subjects enrolled (Cohort-1, n=10; Cohort-2, n=43). Of these, 43/53 (81.1%) transitioned to LEM at the end of TITR; all 43 (100.0%) entered EXT wherein 41/43 subjects received treatment. Three of these subjects discontinued treatment during EXT, so that 38/41 (92.7%) subjects entered EXT, received treatment and completed EXT. At the end of EXT, 25/41 (61.0%) subjects were receiving LEM10 and 16/41 (39.0%) were receiving LEM5. Based on modal dose (most frequent dose taken during TITR and EXT combined) groups, median time to first dose change was 14.5 days and 36.0 days for LEM5 and LEM10, respectively. The majority of TEAEs were mild/moderate in severity. Across the study (TITR and EXT), more TEAEs occurred with LEM10 than LEM5; the most common TEAEs were somnolence (n=4) and abnormal dreams (n=4). Conclusion Study results support the view that patients can successfully transition directly from ZOL to LEM. LEM was generally well tolerated; the safety profile was consistent with that observed in Phase 3 clinical development. Support (if any) Eisai Inc.

Comparison of the Dosimetric Influence of Applicator Displacement on 2D and 3D Brachytherapy for Cervical Cancer Treatment

To compare the dosimetric influence of applicator displacement on two-dimensional brachytherapy (2D-BT) and three-dimensional brachytherapy (3D-BT) for cervical cancer. Nineteen patients who received computed tomography-guided tandem-and-ovoid (T&O) brachytherapy were retrospectively selected. Both 2D (point-based) and 3D (volume-based) plans with and without virtual applicator displacement in the 3 axes were created for each patient. Dose changes at point A, D90 of the high-risk clinical target volume (HR-CTV) and intermediate-risk CTV (IR-CTV), and the D0.1cc, D1cc, D2cc, and D5cc of organs-at-risk (OARs) caused by applicator displacement were evaluated. Both 2D-BT and 3D-BT plans were sensitive to T&O applicator displacement. The D90 of the CTV and the dose at point A were very sensitive to applicator displacement in the right–left direction ( X-axis). An applicator shift of >2 mm in the X-axis resulted in a change of >5% in the dose at point A and D90 of HR-CTV and IR-CTV. In addition, the doses to the OARs were mostly affected by applicator displacement in the anterior–posterior direction ( Z-axis). A displacement of <1.5 mm in the Z-axis was required to avoid a dose change of >10% for OARs. For both 2D-BT and 3D-BT plans, T&O displacement greater than ± 2 mm in the X-axis or T&O applicator displacement ± 1.5 mm in the Z-axis resulted in significant dose changes to the tumor and OARs. In comparison with 3D-BT plans, 2D-BT plans delivered a higher dose to the tumor, and the OARs received more undesirable doses when applicator displacement occurred. The influence of applicator displacement on the doses to the tumor and OARs differed between 2D-BT and 3D-BT. Physicians should take individual patient differences into account when selecting a brachytherapy plan to mitigate the influence of applicator displacement.

Increased Levels of Platelets and Endothelial-Derived Microparticles in Patients With Non-Valvular Atrial Fibrillation During Rivaroxaban Therapy

It is known that atrial fibrillation (AF) is associated with the procoagulant state. Several studies have reported an increase of circulating microparticles in AF, which may be linked to a hypercoagulable state, atrial thrombosis and thromboembolism. We evaluated in our study alterations in both platelet (PMP, CD42b) and endothelial-derived (EMP, CD144) microparticle levels on anticoagulant therapy with rivaroxaban in nonvalvular AF. After administration of rivaroxaban, PMP levels were increased (median, [IQR] 35.7 [28.8-47.3] vs. 48.4 [30.9-82.8] cells/µL; P = 0.012), along with an increase in EMP levels (14.6 [10.0-18.6] vs. 18.3 [12.9-37.1] cells/µL, P < 0.001). In the multivariable regression analysis, the independent predictor of post-dose change in PMPs was statin therapy (HR −0.43; 95% CI −0.75,−0.10, P = 0.011). The post-dose change in EMPs was also predicted by statin therapy (HR −0.34; 95% CI −0.69, −0.01, P = 0.046). This study showed an increase in both EMPs and PMPs at the peak plasma concentration of rivaroxaban. Statins have promising potential in the prevention of rivaroxaban-related PMP and EMP release. The pro-thrombotic role of PMPs and EMPs during rivaroxaban therapy requires further study.

Real-World Clinical Outcomes of Patients with Myelofibrosis Treated with Ruxolitinib: Evidence from a Multinational Medical Record Review

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia, splenomegaly, and debilitating constitutional symptoms, such as fatigue, night sweats, weight loss, bone pain, and pruritus. Prior to the approval of the selective Janus kinase-2 (JAK2) inhibitor fedratinib for adults with Intermediate (Int)-2 or High-risk MF in 2019, ruxolitinib (RUX) was the only FDA-approved JAK inhibitor and considered standard of care; treatment (tx) options after RUX were limited. Furthermore, although about 60% of pts carry JAK2 mutations, not all patients respond to RUX. The aim of this study was to describe real-world tx patterns and determine unmet need in pts with MF treated with RUX. Methods: We report interim data collected from the UK and USA as part of a global retrospective medical chart review of adult pts with Int-1, Int-2, or High-risk MF who started RUX tx between Jan 2012 and Dec 2016 in the USA, UK, Germany, Spain, Canada, and France, Pts were required to have discontinued RUX prior to data abstraction (Apr-May 2020). Prior tx was allowed, except for allogeneic hematopoietic cell transplantation or JAK2 inhibitor trial participation. Study measures included pt and tx characteristics at RUX initiation, tx patterns, dose modifications (DMs), and clinical outcomes. The rate of DMs (decrease or increase) during the first 6 months of tx was assessed. Recommended dose (REC) as per US FDA label of RUX was determined via baseline platelet count; atypical dose (ATY) was defined as non-REC RUX. The Kaplan-Meier method was used to estimate median overall survival (OS) from start of RUX tx. Descriptive statistics are used in this report. Results: A total of 183 pts (USA: 105, UK: 78) were included in the analysis. Mean age at diagnosis was 63 years, 69% were male, and 82% were White. Most pts had primary MF (84%), Int-2-risk disease (51%), and JAK2 V617F driver mutation (67%). RUX was first-line MF tx in 100 pts (55%). Of 140 pts with baseline platelet counts, 46% started on REC RUX, and 54% started ATY RUX. Of pts who initiated ATY RUX, those with platelet count below 200 ×109/L were more likely to receive a higher dose; those with a platelet count above 200 ×109/L, were more likely to receive a lower dose. The median time from diagnosis to RUX initiation overall was 1.3 months (mos); this was shorter in pts initiated on REC RUX and longer in pts initiated on ATY RUX (Table). The median duration of tx (DoT) was higher for pts who initiated ATY RUX vs REC RUX (Table). Among pts who had a dose change (n = 61), change in platelet/neutrophil count (43%), and inadequate response (33%) were the main reasons for the first dose change; dose changes due to toxicity were more common with ATY RUX (33%) vs REC RUX (5%). Eighty-six pts (47%) had clinician-defined inadequate response or progressed on RUX. Pts starting ATY RUX (63% vs 39% for REC RUX) or having a DM within 6 mos of initiation (59% vs 49% for no DM) had a higher proportion of progressive disease (PD). Of those with inadequate response/PD, 69% discontinued RUX and 22% continued RUX due to lack of other effective tx. Twenty-eight percent of pts that started REC RUX discontinued RUX due to experiencing no additional clinical benefit after initial improvement; for pts who started ATY RUX, progression due to anemia (33%) was the main reason for discontinuation. In pts who did not discontinue RUX immediately after inadequate response/PD, median time to RUX discontinuation from inadequate response/PD was higher in pts who received ATY RUX vs REC RUX (6.1 vs 1.9 mos). Of 164 evaluable pts, 32 (20%) received post-RUX tx, most commonly hydroxyurea (28%) or lenalidomide (27%, USA only). Median OS since RUX initiation was 44.2 mos. OS was shorter in pts who started ATY vs REC RUX (40.9 vs 43.1 mos) and those who had a DM vs no DM within 6 mos (38.6 vs 43.0). The most common causes of death were PD (34%) and progression to AML (19%) - pts who received DMs within the first 6 mos were more likely to die from progression to AML (27%) vs those with no DMs (19%). Conclusions: In this population of adults with MF, we provide observational data that indicates DMs, including starting ATY RUX at higher or lower than REC doses, may be associated with poorer survival outcomes and higher rates of discontinuation due to PD. Relatively few pts received subsequent tx after discontinuing RUX, underscoring a significant unmet need for newer and more effective tx for MF. Disclosures Passamonti: Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau. Heidel:Novartis: Consultancy, Honoraria, Research Funding. Parikh:RTI Health Solutions: Other: I am a full-time employee of RTI Health Solutions, which received research funding from BMS to perform this study. RTI Health Solutions is a unit of Research Triangle Institute, an independent, nonprofit, research organization that does work for govern. Tang:BMS: Current Employment, Current equity holder in publicly-traded company. Lahue:BMS: Consultancy; Alkemi LLC: Current Employment. Nadal:BMS: Current Employment. Davis:RTI Health Solutions: Other: I am a full-time employee of RTI Health Solutions, which received research funding from BMS to perform this study. RTI Health Solutions is a unit of Research Triangle Institute, an independent, nonprofit, research organization that does work for govern; BMS, Astra Zeneca, Vertex, Novartis, Esai, United Therapeutics, Pfizer: Research Funding. Ajmera:RTI Health Solutions: Current Employment. Kee:Bristol Myers Squibb: Current Employment. Abraham:BMS: Current Employment, Current equity holder in publicly-traded company.