Dose Titration Research Articles

Changes in Hepatic Density Due to Oral Amiodarone-induced Liver injury Shown by Computed Tomography.

Amiodarone is an antiarrhythmic drug that is widely used for atrial fibrillation and other refractory arrhythmias. Although beneficial, its long-term administration is associated with adverse effects on various organs. One patient presented with amiodarone-induced liver injury, which led to liver failure. Computed tomography revealed a gradual increase in hepatic density over a long period following the initiation of amiodarone. Despite the discontinuation of the drug, the patient developed hepatic encephalopathy and subsequently died. This outcome highlights the drug's extended half-life, which caused persistent end-organ damage even after its withdrawal. Drug titration to the lowest effective dose and careful monitoring of annual liver function tests are important.

Mavacamten in Patients With Hypertrophic Cardiomyopathy Referred for Septal Reduction: Week 128 Results from VALOR-HCM

Background: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), VALOR-HCM trial (Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive HCM Who Are Eligible for Septal Reduction Therapy [URL: https://clinicaltrials.gov; Unique identifier: NCT04349072]) reported that mavacamten reduced the short-term need for septal reduction therapy (SRT). The current report examined the longer-term effect of mavacamten through end of treatment at week 128. Methods: A double-blind randomized placebo-controlled multicenter trial at 19 sites in the United States included symptomatic obstructive HCM patients referred for SRT (enrollment July 2020 through October 2021). The group initially randomized to mavacamten continued the drug for 128 weeks and the placebo to mavacamten group from week 16 to 128 (112-week exposure). Dose titrations were performed using echocardiographic left ventricular outflow tract gradient and left ventricular ejection fraction measurements. The principal end point was proportion of patients proceeding with SRT or remaining guideline-eligible at week 128. Results: At week 128, 17 of 108 (15.7%) patients in the total study sample met the composite end point (7 underwent SRT, 1 was SRT-eligible, and 9 SRT-status unevaluable). Additionally, 87 of 108 (80.5%) patients demonstrated ≥1 New York Heart Association class improvement by week 128, and 52 of 108 (48.1%) demonstrated ≥2, with a sustained reduction in resting and Valsalva left ventricular outflow tract gradients of 38.2 mm Hg and 59.4 mm Hg, respectively. Ninety-five of 108 (88%) patients transitioned to commercial mavacamten. Overall, 15 of 108 (13.8%) patients (5.41 per 100 patient-years) had an left ventricular ejection fraction <50% (2 with left ventricular ejection fraction ≤30%; 1 death). Of these, 12 of 15 (80%) continued treatment. New-onset atrial fibrillation occurred in 11 (10.2%) patients (4.55 per 100 patient-years). Conclusions: In severely symptomatic obstructive HCM patients, sustained freedom from SRT was observed at 128 weeks, with nearly 90% patients remaining on long-term mavacamten.

Improving hospital care for people who use drugs: deliberative process development of a clinical guideline for opioid withdrawal management

BackgroundManagement of opioid withdrawal in hospital settings is crucial to improve treatment completion and health outcomes among patients who use opioids, such as heroin. Evidence-based clinical guidelines can support responsive provision of opioid substitution therapy (OST). In England there is no standardised application of guidance for substance dependence management across National Health Service (NHS) Hospitals. A recent review of NHS hospital policies identified varying approaches to managing opioid withdrawal and procedural barriers to timely medication.ObjectiveTo develop a clinical guideline for opioid withdrawal management in acute NHS hospital trusts to be tested and evaluated as part of the iHOST (Improving Hospital Opioid Substitution Therapy) research intervention.MethodsWe undertook a deliberative guideline development process. The University London College Hospital (UCLH) substance dependence guideline was used as a template, with key points of revision informed by evidence review, consultations with hospital staff and people with opioid dependence. A multidisciplinary working group deliberated evidence statements to develop recommendations. These were reviewed by an oversight committee comprising representatives from key stakeholder organisations. The team authored the guideline with iterative review by the oversight committee, key stakeholders and UCLH clinical governance committees.ResultsDeliberation focused on three key domains: (1) identifying opioid dependence and promptly continuing existing OST prescriptions; (2) initiating or re-titrating OST; (3) ensuring safety and continuity of care at discharge. Changes to the UCLH guideline included removal of mandatory urine drug testing prior to OST; increasing initial methadone titration dose; and provision for a higher day-one titration dose when specific safety criteria are met. A new titration schedule for sublingual buprenorphine was incorporated. Discharge planning to ensure continuity of community care and reduce risk of opioid overdose was emphasised, with allowance for bridging prescriptions of OST and naloxone provision on hospital discharge.ConclusionThe iHOST clinical guideline aims to remove procedural barriers to opioid withdrawal management for hospital inpatients. It is intended to be implemented by other NHS hospitals, which could improve access to OST and reduce discrepancies in treatment access and completion.Study registrationISRCTN47320412 https://doi.org/10.1186/ISRCTN47320412.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Evaluation of continued 2-monthly or annual urate monitoring in gout: an extension of the GoutSMART randomised controlled feasibility trial

Aim: Improved outcomes for patients with gout are associated with reduced urate levels and many guidelines recommend regular urate monitoring. There is no consensus on how frequently monitoring should be performed, and so we have used a supported self-management approach which incorporates urate self-testing to evaluate 2-monthly urate monitoring compared to annual monitoring. Methods: This study was an extension of a 12-month feasibility trial in 60 gout patients randomised 2:1 to support gout self-management or usual care. Participants exiting the self-management arm were offered 2-monthly urate monitoring, with usual care participants offered annual monitoring. Additional participants were randomised 1:1 to either arm. All participants were offered initial dose titration to a urate target of 0.3 mmol/L. The primary outcome was the proportion of participants with urate ≤ 0.36 mmol/L at 24 months with an intention-to-treat analysis. Results: Between September 2020, and September 2021, 67 patients were enrolled. The mean age was 55.5 (SD 14.0) years. 61 (91%) self-reported as cisgender male, 5 (7.5%) as cisgender female and 1 (1.5%) as transgender female. 62 (92.5%) were White, 4 (6.0%) were Asian and 1 (1.5%) was Black. 40 participants were allocated to 2-monthly monitoring (including 10 new participants), and 27 participants to annual monitoring (including 12 new participants). The primary study outcome of urate ≤ 0.36 mmol/L at 24 months was achieved by 38 (95%) 2-monthly monitoring participants, compared to 17 (62.9%) annual monitoring participants (risk difference 0.32 [95% CI 0.13 to 0.52]; p = 0.0021). 5 (7.5%) participants withdrew with 4 allocated to annual monitoring. 2 annual monitoring participants died. Conclusions: 2-monthly monitoring of urate is associated with improved maintenance of urate targets after 2 years compared to annual monitoring, a result influenced by an increased withdrawal rate amongst annual monitoring participants. Further trials evaluating the cost-effectiveness and optimal frequency of urate monitoring are now needed (ClinicalTrials.gov identifier: NCT03274063).

DDEL-07. EFFICACY OF TEMOZOLOMIDE IN MEDULLOBLASTOMA PATIENTS: REVIEW OF SERIES OF TWO ADULT PATIENTS WITH RECENT UPDATES IN LITERATURE

Abstract Medulloblastoma is a primary malignant CNS tumor commonly seen in children and rarely in adults (20% vs 1% of all primary brain tumors). Maximal safe resection and craniospinal irradiation followed by adjuvant chemotherapy have proven to be an effective treatment in children. Due to insufficient data available in adult patients, it is also the usual approach in them despite unclear long-term outcomes. Standard chemotherapeutic regimens consisting of vincristine, cisplatin, and lomustine are known to cause greater toxicity in adults making adequate dose titration a challenge. Temozolomide is a second-generation cytotoxic alkylating agent with favorable CNS penetration. It is a potential alternative that has yielded superior results in treating gliomas and preventing recurrence along with minimal toxicity. We discuss a series of two adult medulloblastoma cases which were given 24 cycles of Temozolomide monotherapy over two years following surgical resection and craniospinal irradiation. Serial MRIs did not report any signs of recurrence rendering one case cancer-free for seventeen years and the other for ten. Minimal toxicity in the form of nausea, vomiting, headache, and reversible, temporary pancytopenia was seen in contrast to other agents. Improved survival with minimal toxicity was demonstrated in both cases proving the efficacy of Temozolomide as adjuvant chemotherapy for adult Medulloblastoma. While a regimen of Temozolomide is recommended for recurrent Medulloblastoma, there is no optimal regimen available for initially diagnosed, localized tumors, especially in adults. Multi-institutional clinical trials are required to study its role as a monotherapy during an early yet critical phase of management.

Phase 3 Open-Label Study Evaluating the Efficacy and Safety of Mavacamten in Japanese Adults With Obstructive Hypertrophic Cardiomyopathy - The HORIZON-HCM Study.

Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear. HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6-20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline -60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study. In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

Clozapine Toxicity Predictor: Deep neural network model predicting clozapine toxicity and its therapeutic dose range

Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients with treatment-refractory patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop.

Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain.

Despite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects of stiripentol use remain challenging in clinical practice, such as dose titration and the adjustment of concomitant antiseizure medications (ASMs) to prevent potential adverse effects. To (1) provide practical recommendations on the initiation of stiripentol treatment in patients with DS, (2) evaluate its effectiveness in the patient, and (3) guide the management of drug interactions and other aspects of treatment monitoring. Six Spanish neurologists (the authors) with expertise in the management of pediatric and adult patients with DS held a meeting in early 2024 to develop expert recommendations regarding the use of stiripentol in DS, based on a review of the literature and their common clinical experience. According to these recommendations, stiripentol can be administered to patients with DS of any age, although its initiation and titration vary according to age group. Individualized adjustment of concomitant ASMs, such as valproic acid and clobazam or drugs specifically for DS (i.e., fenfluramine), at initiation and during stiripentol treatment, can mitigate drug interactions, thereby increasing the long-term tolerability of stiripentol treatment. In specific cases, stiripentol doses of>50 mg/kg/day may be contemplated, and acute stiripentol administration may be considered to control refractory status epilepticus. Blood tests should be performed before starting stiripentol, at 3, 6, and 12 months after starting treatment, and then annually, except in the event of adverse effects, when additional testing may be necessary. Most adverse effects can be adequately managed by adjusting concomitant medications. These practical recommendations may be easily adapted for use in different countries, and should increase physicians' confidence in the initiation and monitoring of stiripentol treatment, thus facilitating effective management of patients with DS and improving clinical outcomes.

Effect of Obesity on Pharmacokinetics of Transdermal Fentanyl: Single-Center Retrospective Study and Animal Study

A retrospective study and an animal study were conducted to investigate factors affecting the transdermal fentanyl dose to achieve adequate pain relief in patients switched from other opioids. In the retrospective study, patient factors were included as gender, age, body mass index (BMI), and serum albumin concentration. In obese (BMI > 25) patients, the post-titration dose of transdermal fentanyl was significantly lower than in normal (BMI 18.5-25) patients despite the initial dose was the same. To support this unexpected finding, fentanyl was administered intravenously and transdermally to Zucker (fa/fa) rats as an obese model and Zucker (+/+) rats as a control. No difference in systemic clearance (CLtot) after intravenous administration was observed between the two groups. However, transdermal bioavailability (F) and fentanyl release ratio from the formulation (Fa) were significantly increased in Zucker (fa/fa) rats compared to Zucker (+/+) rats. Skin availability (Fskin), calculated as F divided by Fa, was also significantly increased. These results indicated that obesity should be considered as a factor in the titration of transdermal fentanyl dose.

The Utility of Electroencephalograhy in Guiding General Anesthesia in Children.

Traditional pediatric anesthetic dosing using pharmacokinetic estimates based on age and weight is often imprecise, frequently leading to oversedation. Intraoperative electroencephalography (EEG) allows visualization of the brain's response to anesthetic agents in real time, facilitating precise titration of anesthetic drug doses optimized for the individual child. The goal of EEG-guided anesthesia management is to maintain an optimal state of hypnosis during various stages of the procedure while minimizing hemodynamic instability and other adverse effects of anesthesia. This is especially important in children with less predictable anesthetic requirements, such as children with atypical neurodevelopment, altered levels of consciousness before anesthesia, or those receiving total intravenous anesthesia, neuromuscular blockers, or a combination of anesthetic agents with different mechanisms of actions. Children with limited cardiorespiratory reserves and those undergoing high-risk procedures such as cardiopulmonary bypass also benefit from EEG guidance as they have a narrower therapeutic window for optimal anesthetic dosing. Various processed EEG (pEEG) monitors are available for intraoperative monitoring in children. These monitors display a pEEG index based on the manufacturer's algorithm, purportedly indicating the patient's hypnotic state. Due to differences in developmental neurophysiology and EEG dynamics in children, pEEG indices may not always reliably indicate the hypnotic state, especially in neonates and infants. Learning to interpret nonproprietary EEG parameters including the raw EEG, spectral-edge frequency 95% (SEF95), and density spectral array can prevent overreliance on pEEG indices. This review provides an overview of the advantages of EEG guidance during clinical anesthesia, including potential reduction in anesthetic dosage, prevention of EEG suppression, and reduction in peri-operative adverse events. We describe the use of nonproprietary EEG parameters in guiding anesthesia in children for various clinical end points including laryngoscopy, surgical incision, and maintenance of anesthesia, as well as sedation. We illustrate these principles with various case examples commonly encountered during pediatric anesthesia. Lastly, we discuss strategies to expand intraoperative EEG monitoring in children through education and training programs, as well as advocate for further research to assess clinical outcomes associated with EEG guidance to support its routine use in clinical care.

Clinical application of biomarkers in obstructive hypertrophic cardiomyopathy: insights from SEQUOIA-HCM

Abstract Background Multiple studies show that circulating cardiac biomarkers, N-terminal pro-B type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin I (hs-cTnI) are associated with key pathophysiological processes and clinical outcomes in obstructive hypertrophic cardiomyopathy (oHCM). Herein we describe the impact of aficamten on cardiac biomarkers in SEQUOIA-HCM (NCT05186818). Purpose In this pre-specified analysis, we describe associations between baseline NT-proBNP and hs-cTnI concentrations and assess the relationship between changes after treatment with aficamten and trial endpoints. Methods Patients with oHCM in NYHA Class II-III, were randomized 1:1 to 24 weeks of daily aficamten (5–20 mg, n=142) or placebo (n=140). Aficamten dose was adjusted to achieve Valsalva left ventricular outflow tract gradient (LVOT-G) &amp;lt;30 mmHg while maintaining left ventricular ejection fraction (LVEF) ≥50%. Peak oxygen consumption (pVO2) was measured by cardiopulmonary exercise testing at baseline and week 24. Cardiac biomarkers were measured at baseline, each dose titration (weeks 2, 4, and 6), every 4 weeks during treatment and after 4 weeks drug washout. Multivariable regression analysis was used to identify significant predictors of baseline biomarker values. Joint modeling and mediation analysis was used to determine how much of the treatment effect was indirectly mediated by NT-proBNP and hs-cTnI. Results In 282 symptomatic oHCM patients (mean age 59 years, 41% female), the median (IQR) NT-proBNP was 788 ng/L (346, 1699) and hs-cTnI was 12 ng/L (9, 27). At baseline, LVOT-G modestly correlated with NT-proBNP, rho = 0.26 (p&amp;lt;0.001) but not hs-cTnI, rho = 0.06 (p=0.36). Predictors of baseline biomarker values are summarized in Table 1. Compared to placebo, aficamten treatment was associated with an early relative reduction from baseline at week 8 in NT-proBNP (-79% (95% CI -83%, -76%, p&amp;lt;0.001) and in hs-cTnI -41% (-49%, -32%), p&amp;lt;0.001. This magnitude of change persisted to week 24 with biomarker return to baseline after aficamten washout (Figure 1). The mediation analysis suggested that NT-proBNP reduction over the 24-week treatment period reflected 101% (41%, 195%) of aficamten’s effect on pVO2. In contrast hs-cTnI reduction reflected 3% (-18%, 30%) of aficamten’s effect on pVO2. Conclusions Concentrations of NT-proBNP and hs-cTnI are associated with clinically relevant echocardiographic variables in oHCM. Compared with placebo, aficamten treatment markedly reduced plasma NT-proBNP and hs-cTnI concentrations, evident from week 2 and persisting until the end of treatment. NT-proBNP reduction may link LVOT-G with reduced exercise capacity in oHCM. These data support the use of biomarkers as a tool for managing patients with oHCM in order to monitor response to aficamten therapy.Effect of aficamten on biomarkersPredictors of baseline biomarkers

Real-world experience with mavacamten in obstructive hypertrophic cardiomyopathy: observations from a tertiary care center

Abstract Background In symptomatic obstructive hypertrophic cardiomyopathy (oHCM) patients, mavacamten is commercially approved to help improve left ventricular (LV) outflow tract (LVOT) gradients, symptoms, and reduce eligibility for septal reduction therapy (SRT) under the risk evaluation and mitigation strategy (REMS) program. We sought to prospectively report the initial real-world clinical experience with the use of commercially available mavacamten in a multi-hospital tertiary healthcare system. Methods We studied the first 150 consecutive oHCM patients (mean age 65 years, 53% women, 83% on betablockers and 61% in New York Heart Association [NYHA] class III) who were initiated on 5 mg of mavacamten with dose titrations using symptom assessment and echocardiographic measurements of LVOT gradient and LV ejection fraction (LVEF) measurements. We measured changes in NYHA class, LVEF, LVOT gradients (resting and Valsalva) at baseline, 4, 8 and 12 weeks. Results At 261±143 days (range of 31-571 days), 69 (46%) patients had ≥1 NYHA class, 27 (18%) additional patients had ≥2 NYHA class improvement and 40 (27%) reported a no change in symptoms. The mean LVOT gradient at rest decreased from 41±33 mmHg at baseline to 16±17 mmHg at 4 weeks, 16±16 mmHg at 8 weeks and 15±16 mmHg at 12 weeks. The mean drop in resting LVOT gradient from baseline to last follow-up was 26±3 mmHg (p&amp;lt;0.0001). The mean Valsalva LVOT gradient decreased from 72±43 mmHg at baseline to 29±31 mmHg at 4 weeks, 29±28 mmHg at 8 weeks and 30±29 mmHg at 12 weeks (p&amp;lt;0.001). The mean reduction in post Valsalva LVOT gradient from baseline to last follow-up was 43±4 mmHg (p&amp;lt;0.0001). At baseline, 100% patients had Valsalva LVOT gradients ≥ 30 mm Hg and 142 (95%) had ≥ 50 mm Hg. After initiation of mavacamten therapy, Valsalva LVOT gradient ≥ 30 mm Hg was observed in 44/150 (29%) at 4 weeks, 40/141 (28%) at 8 weeks and 41/136 (30%) at 12 weeks. In 40 patients who reported no symptomatic improvement, the mean Valsalva LVOT gradient decreased from 73±39 mmHg at baseline to 34± 27 mmHg at 4 weeks, 35±28 mmHg at 8 weeks and 30±24 mmHg at 12 weeks (P&amp;lt;0.001). The mean LVEF at baseline was 66±6% and changed to 64±5% at 4 weeks, 63±5% at 8 weeks and 62±7% at 12 weeks (p&amp;lt;0.0001). No patient underwent SRT, developed LVEF ≤30% or developed heart failure requiring admission. Three (2%) patients needed temporary interruption of mavacamten due to LVEF&amp;lt;50. During follow up, dose reduction or discontinuation of background HCM therapy (betablockers, calcium channel blockers and disopyramide) occurred in 33 (22%) patients. The breakdown of various drug doses of mavacamten, at last follow-up, is as follows: 2.5 mg (n=29, 19%), 5 mg (n=80, 53%), 10 mg (n=37, 25%) and 15 mg (n=3, 2%). Conclusions In a real-world study in symptomatic oHCM patients at a multi-hospital tertiary care referral center, we demonstrate the efficacy and safety of prescribing mavacamten under the REMS program.

Long-term safety and efficacy of mavacamten in obstructive hypertrophic cardiomyopathy: up to 3.5-year follow-up results of the EXPLORER cohort of MAVA-Long-Term Extension study

Abstract Introduction Mavacamten safety and efficacy in patients with obstructive hypertrophic cardiomyopathy (HCM) was demonstrated in the phase 3 EXPLORER-HCM trial. Long-term safety and efficacy of mavacamten in patients with obstructive HCM is being studied in the MAVA-Long-Term Extension (LTE) study (NCT03723655). Purpose To present long-term safety and efficacy data from the EXPLORER cohort of MAVA-LTE up to week 180 (data cutoff: August 31, 2023). Methods Patients who completed EXPLORER-HCM could enroll in MAVA-LTE following washout. All patients received mavacamten 5 mg at baseline; dose titration to 2.5, 10, or 15 mg was based on site-read echocardiographic evaluation of Valsalva left ventricular outflow tract (LVOT) gradient and left ventricular ejection fraction (LVEF). Following titration, patients were assessed at 12-week intervals between weeks 24 to 156; week 180 was the first visit following a 24-week interval. Results At the data cutoff, 211 of 231 patients who enrolled in MAVA-LTE were on treatment; 185 and 99 patients had reached week 156 and 180, respectively (median [interquartile range (IQR)] time on study: 166 [160–189] weeks; total exposure: 739 patient-years). Sustained improvements from baseline to weeks 156 and 180 were observed in mean (standard deviation [SD]) resting LVOT gradient (−40.2 [32.8] mmHg, n=187; and −40.3 [32.7] mmHg, n=94; respectively), Valsalva LVOT gradient (−55.3 [37.3] mmHg, n=184; and −55.3 [33.7] mmHg, n=91) (Figure 1), and median (IQR) N-terminal pro B-type natriuretic peptide levels (−504 [−1160, −143] ng/L, n=179; and −562 [−1162.5, −209] ng/L, n=88). Improvements from baseline to weeks 144 and 180 were sustained in mean (SD) left atrial volume index (−3.5 [10.4] mL/m2, n=193; and −5.5 [9.7] mL/m2, n=62; respectively). At week 156 and 180, 53.5% and 66.3% of patients, respectively, were in New York Heart Association class I. Mean (SD) LVEF decreased from baseline to week 180 (−11.0% [8.9%]; n=93) but the mean (63.9%) remained within normal range. Overall, 33 patients (14.3%) experienced atrial fibrillation, 14 patients (6.1%) experienced cardiac failure episodes, 13 patients (5.6%) permanently discontinued treatment owing to adverse events and 20 patients (8.7%) experienced transient reductions in LVEF &amp;lt; 50% (range: 30–48%), of whom 6 (2.6%) experienced LVEF &amp;lt; 40% (Figure 2). Of these 20 patients (13 from the placebo group in EXPLORER-HCM), all recovered LVEF ≥ 50% following treatment interruption and 14 reinitiated medication. In total, 5 patients died during the study (all deaths unrelated to mavacamten). Conclusions Long-term mavacamten treatment in patients with obstructive HCM resulted in sustained improvements in echocardiographic measures, symptoms, and biomarkers. Treatment was well-tolerated; no new safety signals were observed. Transient and reversible reductions in LVEF were observed in a small proportion of patients during long-term therapy.

Do more with less? Impact of personalized very low doses of amlodipine in the PERSONAL-CovidBP trial

Abstract Introduction The Personal-CovidBP study1 tested remote patient use of a drug-device combination of a smartphone application (App) to record blood pressure (BP), novel personalized milligram-by-milligram drug (amlodipine) dose, and relevant side effects daily during the COVID-19 pandemic. Purpose In supplementary data analyses, we examined the effect of using small doses (1 mg) and small increments (1-2 mg) of amlodipine on the BP response and side effects. Methods In this community-based trial with remote monitoring and remote medical management from the investigational site, hypertensive participants aged 18 years + with poor BP control (prior 7 day mean of 135 mmHg systolic BP or above and/or 85 mmHg diastolic BP and above) were enrolled to intervention with open label dose titration over 14 weeks, allowing personalized dosing of liquid amlodipine (1–2 mg steps from 1–10 mg daily). Results 205 patients were enrolled into the intervention group between October 2020 and July 2021. Average BP in intervention fell from 141/87 to 131/81 (difference −10/6 p &amp;lt; 0.001). Even low doses or small increments: 1 or 2 mg amlodipine or 5 mg to 6 mg, produced meaningful BP responses. Here we report that the addition of amlodipine during the study reduced blood pressure regardless of being amlodipine naive at baseline (n=141), or receiving amlodipine 2.5mg or 5mg at baseline (n=62). The response slopes were comparable, and mean reductions in SBP were consistent across groups: -11.7 (95% CI: -12.9 to -10.6); -9.4 (-11.1 to -7.7); respectively (Figure 1). For the amlodipine naive, the majority (76%) achieved BP control at low doses (&amp;lt;1 to 3mg) with occurrence of side effects increasing with dose (Figure 2). Conclusions Our real-world remote care study demonstrated that very low doses of amlodipine as little as 1 mg were effective and for 1mg-3mg gained BP control in the majority and were associated with fewer side effects which is consistent with previous meta-analyses.2 Personalized treatment titration was effective even at very low doses and also regardless of whether amlodipine naive or not at baseline.Changes in SBP- baseline amlodipine useAmlodipine dose at control vs oedema

Masked hypotension in patients with heart failure

Abstract Background Hypotension limits the up-titration of guideline-directed medical therapies (GDMTs) and correlates with poor prognosis in patients with heart failure. The value of ambulatory blood pressure monitoring (ABPM) in heart failure patients and its association with GDMTs optimization and clinical outcomes were undetermined. Methods REM-HF (Risk Evaluation and Management in Heart Failure) is a multicenter, prospective observational cohort. Our study screened patients from REM-HF who were hospitalized for incident HF and newly initiated GDMTs between April 2018 and December 2022. Eligible participants conducted a 24-hour ABPM before discharge and were followed-up as the cohort routine. GDMTs target dose achievement and dose trajectories were assessed at 3-month visit. The primary outcome was a composite of all-cause mortality and heart failure readmission. Results On adjusted restricted cubic spline analysis, office SBP demonstrated a U-shape relationship with the primary outcome (P for nonlinearity=0.003), while 24-hour SBP was linear (P for nonlinearity=0.338). The risk-related threshold of ambulatory and office systolic hypotension was defined as corresponding SBP &amp;lt; 120 mmHg accordingly. Combining these two measurements together, we described three blood pressure status as sustained hypotension (s-hypo, both SBP &amp;lt; 120 mmHg), masked hypotension (m-hypo, 24h SBP &amp;lt; 120 mmHg while office SBP ≥ 120mmHg), and non-hypotension (n-hypo). Among the 491 patients included, 124 (25.3%), 151 (30.8%) and 216 (44.0%) had s-hypo, m-hypo, and n-hypo, respectively. The m-hypo group showed similar clinical features as the s-hypo subjects, including more serious left ventricle remodeling and worse cardiac function. After the GDMTs dose titration, either patients with s-hypo or m-hypo were as unlikely to achieve target dose as the non-hypotensives (OR for s-hypo 0.42, 95%CI 0.19-0.95, P=0.038; OR for m-hypo 0.39, 95%CI 0.19-0.80, P=0.011). During a median follow-up of 693 days, the adjusted risk of primary outcome was higher in the s-hypo group and m-hypo group compared with the non-hypo group (HR for s-hypo 2.47, 95%CI 1.54-3.96, P&amp;lt;0.001; HR for m-hypo 1.68, 95%CI 1.06-2.65, P=0.027). No significant differences were found in target dose achievement and clinical outcomes between the s-hypo and m-hypo groups. Conclusion Masked systolic hypotension can occur in nearly one-third of new-onset HF patients. Patients with m-hypo and s-hypo exhibit similar clinical characteristics, both associated with GDMTs intolerance and adverse outcomes, suggesting m-hypo deserves recognition as a discrete entity. ABPM provides a more comprehensive view of patients’ blood pressure status by identifying this population.

Nonlinear mixed-effects modeling as a method for causal inference to predict exposures under desired within-subject dose titration schemes.

The ICH E9 (R1) guidance and the related estimand framework propose to clearly define and separate the clinical question of interest formulated as estimand from the estimation method. With that it becomes important to assess the validity of the estimation method and the assumptions that must be made. When going beyond the intention to treat analyses that can rely on randomization, causal inference is usually used to discuss the validity of estimation methods for the estimand of interest. In pharmacometrics, mixed-effects models are routinely used to analyze longitudinal clinical trial data; however, they are rarely discussed as a method for causal inference. Here, we evaluate nonlinear mixed-effects modeling and simulation (NLME M&S) in the context of causal inference as a standardization method for longitudinal data in the presence of confounders. Standardization is a well-known method in causal inference to correct for confounding by analyzing and combining results from subgroups of patients. We show that nonlinear mixed-effects modeling is a particular implementation of standardization that conditions on individual parameters described by the random effects of the mixed-effects model. As an example, we use a simulated clinical trial with within-subject dose titration. Being interested in the outcome of the hypothetical situation that patients adhere to the planned treatment schedule, we put assumptions in a causal diagram. From the causal diagram, conditional independence assumptions are derived either by conditioning on the individual parameters or on earlier outcomes. With both conditional independencies unbiased estimates can be obtained.

Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Importance of Ultraviolet-C (UV-C) Emitter Configuration for Clostridioides difficile Attenuation.

The impact of ultraviolet-C (UV-C) emitter configuration on pathogen attenuation has not been assessed. We hypothesized that emitter configuration would impact UV-C efficacy forClostridioides difficile(C. difficile) attenuation. C. difficilecarriers(ReadyNowTM Test Carriers, Stratix Labs Corporation, Saint Paul, MN) inoculated with > 108 C. difficile American Type Culture Collection (ATCC) 43593 (according to American Society for Testing and Materials (ASTM) 3135 standards) were obtained, and the following experiments were conducted from April to August of 2023. Each of the three carriers along with three calibrated radiometers (ILT1270, International Light Technologies, Peabody, MA) were mounted on an aluminum stand at positions A (left of center of stand), B (center of stand), and C (right of center of stand). The stand was positioned at 9 feet (2.74 m) from and directly ahead of UV-C emitters utilizing low-pressure mercury gas UV-C lamps (Surfacide, Waukesha, WI). Five UV-C emitter configurations were assessed; (1) three emitters with a triangular configuration about the stand and each rotating 360 degrees, (2) one emitter facing the stand and rotating 360 degrees, (3) three emitters facing the stand in a linear configuration and each rotating 5 degrees, (4) one emitter facing the stand and rotating 5 degrees, and (5) one emitter facing the stand and rotating 90 degrees. Three serial experiments were conducted. The first experiment used a dose titration curve to identify the minimally effective irradiation dose (mean and standard deviation mJ/cm2) to achieve no growth (6-log reduction) in C. difficile counts with direct irradiation exposure. The second experiment involved assessing the relative efficacy of the five emitter configurations with the use of the minimally effective dose in attenuating polycarbonate C. difficile carrierspositionedat 25.5 and 69.5 inches (64.77 to 176.53 cm) from the floor and oriented vertically to the emitters. The third experiment evaluated the relative efficacy of the five configurations for polycarbonate and textured plastic C. difficile carriers positioned at 25.5 or 58.5 inches (64.77 to 148.59 cm) from the floor and with a 45-degree or horizontal orientation to the emitters. We assessed residual anaerobic bacterial contamination for three intensive care unit (ICU) rooms to ascertain clinical applications of study results. The minimally effective dose for polycarbonate C. difficile carriers with direct exposurewas 432.28 ± 2.12 mJ/cm2. Configurations one through five achieveda > 4-log reduction when the minimally effective dose was delivered to polycarbonate C. difficile carriers that were positioned at 9 feet from the emitters, 25.5 or 69.5 inches from the floor, and with vertical orientation to the emitters. When C. difficile carriers were changed to textured plastic, orientation to the emitters was changed to horizontal or 45 degrees, and height from the floor was changed to 25.5 and 58.5 inches, the log reductions achieved by configuration one through five were 1.61, 0.61, 0.79, 1.15, and 0.98, respectively, with configuration one achieving a greater log reduction than two (P = 0.0137).In each of the three ICU rooms,at least one of nine sampled locations returned ≥ 500 anaerobic CFU, indicating the need for at least a 0.7-log reduction (500 to 99 CFU). UV-C emitter configuration impacts efficacy in attenuating C. difficile.

Effects and interaction of single nucleotide polymorphisms at the pharmacokinetic/pharmacodynamic site: insights from the Rotterdam study into metformin clinical response and dose titration.

Our study investigated the impact of genetic variations on metformin glycemic response in a cohort from the Rotterdam Study, comprising 14,926 individuals followed for up to 27 years. Among 1285 metformin users of European ancestry, using linear mixed models, we analyzed the association of single nucleotide polymorphisms (SNPs) and a Polygenic Risk Score (PRS) with glycemic response, measured by changes in metformin dosage or HbA1c levels. While individual genetic variants showed no significant association, rs622342 on SLC2A1 correlated with increased glycemic response only in metformin monotherapy patients (β = -2.09, P-value < 0.001). The collective effect of variants, as represented by PRS, weakly correlated with changes in metformin dosage (β = 0.023, P-value = 0.027). Synergistic interaction was observed between rs7124355 and rs8192675. Our findings suggest that while higher PRS correlates with increased metformin dosage, its modest effect size limits clinical utility, emphasizing the need for future research in diverse populations to refine genetic risk models.