Average Baseline Research Articles

Serial changes in left and right ventricular global longitudinal strain in symptomatic obstructive hypertrophic cardiomyopathy treated with mavacamten: insights from VALOR-HCM trial

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, reduces the need for septal reduction therapy with sustained improvement in left ventricular outflow tract gradients and symptoms. As a cardiac myosin inhibitor, mavacamten’s mechanism of action reduces myocardial hypercontractility. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function and can complement left ventricular ejection fraction (LVEF). Objective We sought to assess serial changes in LV and right ventricular (RV)-GLS in patients enrolled in the VALOR-HCM study. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean 60 years, 51% male, LVEF 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). LV and RV-GLS assessment was performed according to the current American and European guideline recommendations using a vendor-neutral post processing software. Non-foreshortened apical (4, 3 and 2-chamber) views were used to obtain peak value of LV-GLS. For RV-GLS, RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. Results Serial changes in LVEF, average LV-GLS, and RV-GLS (4-chamber and free wall) from baseline to week 56 are shown in the Figure. Despite preserved LVEF at baseline, average baseline LV-GLS was abnormal. There were significant and continued improvements in LV-GLS in the total group from baseline to week 56. 12 patients had transient reduction in LVEF (<50%) requiring temporary drug interruption (permanent discontinuation in 3). The LV-GLS in this subgroup was worse at baseline compared to the total study population, with no significant worsening from baseline through week 56. In the overall population, excluding these 12 patients, LV-GLS demonstrated an improvement sustained through week 56. Both free wall and 4-chamber RV-GLS were abnormal at baseline and remained unchanged from baseline to week 56. Conclusions In the VALOR-HCM trial, despite hypercontractile LVEF at baseline, average baseline LV-GLS was worse than normal reference values. Treatment with mavacamten resulted in an improvement in LV-GLS from baseline through Week 56 (with no significant worsening of LV-GLS in the subgroup who experienced any reduction in LVEF <50%), suggesting a favorable long-term impact on regional LV systolic function due to the reduction of cardiac hypercontractility. Additionally, there was no significant detrimental impact on RV systolic function on serial GLS assessment.Serial changes in LV and RV GLS in VALOR

Prognostic impact of echocardiographic predictors of subclinical systolic dysfunction in patients with moderate aortic stenosis

Abstract Introduction Moderate aortic stenosis (AS) marks a critical point in AS severity spectrum, paralleled by significant cardiac structural changes. Concentric left ventricular (LV) hypertrophy, in response to the increased afterload, enables the preservation of a normal ejection fraction (EF) despite significant underlying myocardial dysfunction. Reductions in LVEF may serve as early indicators of the LV's diminished capacity to withstand this increased afterload, potentially leading to LV fibrosis and irreversible myocardial damage. Research has shown that LVEF may not recover in some patients following aortic valve replacement (AVR). Consequently, there is a growing debate concerning higher LVEF thresholds for triggering AVR in patients with severe AS, aiming to intervene before clinical systolic dysfunction ensues and irreversible damage occurs. Meanwhile, a combination of objective indicators may help to identify those patients AS at high risk before a decline in LVEF occurs. Aim To explore the role of baseline left ventricle global longitudinal strain (GLS) and strain rate (SR) as markers of subclinical LV dysfunction, as predictors of LVEF depression, and their impact on survival of patients with moderate AS. Methods Patients with moderate AS and LVEF ≥ 50% at least in 2 echocardiograms were retrospectively identified. Prosthetic and bicuspid valves were excluded. Baseline LV GLS and SR were used as covariates in cox regression models to predict the cumulative incidence of LVEF depression over 5 years and overall survival after multivariable adjustment including time-dependent AVR. Results 574 patients were included (age 76 ± 9 years; 51% female; median follow-up time of 8.97 years). The average baseline aortic peak velocity was 3.4±0.8 m/s, mean pressure gradient was 25±9 mmHg, aortic valve area was 1.1± 0.3 cm2, and LVEF 60±5%. The average GLS was -17±7 % while the peak systolic SR was 1.2 ± 0.5/s. Both baseline GLS (HR= 0.88 for each -1%; 95% CI= 079-0.99; p= 0.04) and SR (HR= 0.89 for each +0.1/s; 95% CI= 0.80-0.99; p=0.03) were associated with 5-year incidence of LVEF depression (<50%). Risk discrimination improved by incorporating SR on top of GLS (increase in area under curve from 0.78 to 0.84; 95% CI= 0.01-0.10; p= 0.04). Furthermore, a nonlinear relation was found between GLS (optimal boundary <-15.8%; p=0.35) and SR (optimal boundary >0.96/s; p=0.34) and overall survival. Conclusions This study identifies baseline GLS and SR as predictors of LVEF depression in moderate AS underscoring their importance in detecting subclinical LV dysfunction. The combination of GLS and SR may enhance the prediction of cardiac function decline, suggesting their potential utility in guiding early intervention strategies. Although their direct relationship with survival needs further exploration, these findings advocate for incorporating GLS and SR in AS management to inform timely AVR decisions and improve patient outcomes.

Non-invasive imaging to guide percutaneous coronary revascularization in chronic total occlusion: a systematic review and meta-analysis

Abstract Background and aims Whether recanalization of coronary chronic total occlusions (CTO) leads to improved patient outcomes is uncertain. We set out to investigate the use of noninvasive imaging modalities to guide patient selection for percutaneous recanalization of coronary chronic total occlusions (CTO-PCI) and its association with outcomes. Methods Systematic review and meta-analysis of studies involving patients undergoing CTO-PCI to detail use of preprocedural non-invasive imaging, change in clinical endpoints and the occurrence of clinical events in these patient cohorts. PubMed and Embase, the Cochrane Database of Systematic Reviews, the PROSPERO database and the Clinical Trials Registry were searched for relevant randomized and observational studies up to May 2023. This study is registered with PROSPERO. The study primary endpoint was a composite of all-cause death and nonfatal myocardial infarction (MI), with a secondary composite endpoint of cardiovascular death, nonfatal MI and target vessel revascularization (TVR). Additional endpoints were individual components of the composite endpoints along with changes in angina burden, LV ejection fraction, ischemic burden, and infarct extent after PCI. Results Of 1264 publications retrieved, 31 studies (26 observational and 5 randomized) were finally included for a total of 7260 patients. Guidance to CTO-PCI varied greatly among included studies, with only a minority implementing routine preprocedural inducible ischemia and myocardial viability assessment. At a median of 3.1 years (range 1-5 years), the primary endpoint occurred at a rate of 3.1 events per 100 patient-years (95%CI: 2.4-3.7). When non-invasive imaging was used to guide CTO-PCI, patients with myocardial ischemia and/or viability, a reduced risk for the primary endpoint was observed (OR 0.3 95%CI 0.2-0.5) compared to CTO-PCI without evidence of myocardial ischemia and/or viability. CTO-PCI was associated with improvements in SAQ summary score, LVEF, reduction of ischemic burden, improvement in myocardial perfusion (all P-values < 0.01), with no change in the burden of myocardial scarring. At meta-regression analysis, a greater improvement in LVEF was observed in studies enrolling patients with lower average baseline LVEF (≤ 45%) (R2 = 63%, p < 0.0001). Conclusions CTO-PCI led to a significant improvement in symptom status (reduction of chest pain) and LV ejection fraction. CTO-PCI guided by the presence of ischemia and/or viability was associated with improved patient outcomes compared with CTO-PCI in the absence of ischemia and/viability, or in patients where non-invasive imaging testing was not performed. Future randomized clinical trials testing whether ischemia and viability-guided CTO-PCI improves clinical outcomes are lacking and warranted.PRISMA Flow diagramGraphical abstract

EFFICACY OF NEOADJUVANT TARGETED THERAPY IN TREATMENT OF PATIENTS WITH LOCALISED CLEAR-CELL RENAL CELL CARCINOMA

Clear-cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, accounting for approximately 75-80% of all renal malignancies. Objectives: The main objective of the study is to find the efficacy of neoadjuvant targeted therapy in the treatment of patients with localised clear-cell renal cell carcinoma. Methods: This prospective study was conducted at Mardan Medical Complex from June 2023 to January 2024. Data were collected from 85 patients. Patients aged>18 years and have a histologically confirmed diagnosis of localized ccRCC were included in the study. Tumor size was required to be 4 cm or larger, but confined to the kidney, corresponding to Stage I to III disease. Results: Data were collected from 85 patients with an average baseline tumour size for the entire cohort was 7.5 cm, and after 12 weeks of treatment, tumours shrank to an average of 5.6 cm, resulting in a mean tumour reduction of 25%. In the sunitinib group, the tumour size decreased from 7.5 cm to 5.55 cm, reflecting a 26% reduction. Similarly, in the pazopanib group, the tumour size was reduced from 7.5 cm to 5.65 cm, with an average reduction of 24%. Conclusion: It is concluded that neoadjuvant targeted therapy, using agents such as sunitinib and pazopanib, effectively reduces tumour size and improves surgical outcomes in patients with localized clear-cell renal cell carcinoma.

Medigap Guaranteed Issue Associated with Medicare Advantage Disenrollment for Beneficiaries Administered a Part B Drug

Abstract While many Medicare beneficiaries are enrolling in Medicare Advantage (MA), some beneficiaries may want to return to traditional Medicare and purchase Medigap, especially beneficiaries that have greater medical needs. Beyond minimal federal regulations, states impose additional regulations that impact Medigap affordability. Beneficiaries in some states have greater difficulty obtaining Medigap coverage because the states where they live allow Medigap insurers to experience rate the beneficiary, which can make Medigap insurance prohibitively expensive. We examined beneficiaries who received physician-administered drugs, which can be expensive and subject to high cost-sharing, to see if disenrollment from MA for these beneficiaries was greater in states with Medigap consumer protection policies levels. In 2020, we find a 1.0% average baseline average probability of MA disenrollment. For beneficiaries that received a physician-administered drug in our sample, the probability of MA disenrollment is 3.7 (95% C I: 2.6-4.8; p<0.001) percentage points higher in Medigap guaranteed issue states compared to states with no protections. We find a greater association between MA disenrollment and Medigap protection policies with higher-cost drugs. These findings suggest that beneficiaries who receive a high-volume and high-spending physician-administered drug are more likely to disenroll from MA back to traditional Medicare when Medigap is more affordable.

Translational Quotient as an Innovative Outcome Parameter to Assess the Effectiveness of Training Methods: A Feasibility Study in Assessing the Baseline Psychiatric Skills of Primary Care Doctors in their Real-world Live Outpatient Clinic

Background: The effectiveness of training methods in medical education is critical, particularly for primary care physicians (PCPs) who frequently encounter psychiatric issues in their practice. Traditional assessment methods often fail to evaluate skill acquisition in real-world clinical practice. The Translational Quotient (TQ) is proposed as an innovative outcome measure to assess PCPs’ ability to apply psychiatric skills in their live outpatient consultation among their general patients. This study aims to evaluate the feasibility of using the TQ in real-world outpatient clinics and to understand the baseline psychiatric skills among PCPs using TQ. Methods: Actively practicing MBBS-qualified PCPs enrolled in the Diploma in Primary Care Psychiatry (DPCP) program across various districts were invited to participate. Baseline TQ assessments were conducted in the PCPs’ live clinics, with psychiatrists observing live consultations either remotely or in-person for the first five consecutive general consultations. Each consultation was scored using a standardized TQ proforma, which evaluated six criteria: elicitation of psychiatric symptoms, clinical reasoning, medication choices, counseling, time management, and overall clinical skills. Results: A total of 25 PCPs participated, with an average baseline TQ score of 15.7% (4.72 out of 30). Most participants (72%) scored 5 or less, highlighting significant gaps in psychiatric skills. Analysis revealed no significant associations between TQ scores and PCP demographics such as age, gender, and prior psychiatric training, but regional differences were noted, with lower scores in Karnataka compared to Bihar. Conclusions: The TQ is a feasible and practical tool for assessing real-world psychiatric skills among PCPs. The baseline scores indicate a pressing need for targeted psychiatric training to bridge the treatment gap in primary care. Future training programs should focus on enhancing diagnostic accuracy, treatment planning, and patient communication to improve mental healthcare outcomes in primary care settings.

Clinical and ultrasound optimization in rheumatoid arthritis for patients in sustained remission, can it work as a new optimization tool?

Some studies have noted that scores relying solely on clinical values to evaluate remission in rheumatoid arthritis (RA) may miss subclinical inflammation, which can lead to exacerbations when therapy is reduced. This opens the possibility of supporting clinical evaluation with imaging studies, one of which is ultrasound (US) evaluation, since it is an accessible tool. Therefore, we have decided to design a study to try to demonstrate the usefulness of US as a complementary measure for the decision-making process in determining the optimization of therapy in patients with RA. A multicenter, blinded, randomized, prospective study was conducted in RA patients meeting 2010 ACR/EULAR criteria for sustained remission by DAS28-ESR, with concomitant CDAI/SDAI evaluation. Patients were classified into clinical and ultrasound groups, with treatment remission based on DAS28 or grayscale synovitis/Doppler values. Ultrasound assessments included grayscale (GS) and power Doppler (PD) for joints (A) and tendons (T). A 12months follow-up was performed, with a subset analyzed at both 18 and 24months. Exacerbation criteria: DAS28-ESR rise > 1.2 or CDAI/SDAI > 16. Across all centers, 78 patients were initially recruited, but only 46 completed the 12-month follow-up, with 28 undergoing further evaluation at 24months. The average baseline DAS28 scores were 1.85 for the clinical group and 1.80 for the ultrasound group. During the study, 18 patients experienced disease exacerbation based on DAS28 score elevation, with 10 in the clinical group and 8 in the ultrasound group. Seven patients experienced disease exacerbation based on CDAI score elevation, all of whom were included in the clinical group. Eight patients showed disease exacerbation based on SDAI score elevation, all in the clinical group. We have demonstrated the utility of ultrasound when optimizing management of rheumatoid arthritis patients. In our patient cohort, ultrasound helps to reduce the number of exacerbations using the SDAI/CDAI index. We highlight the limitations of current assessment methods that rely solely on clinical evaluation, underscore the potential significance of evaluating subclinical synovitis, and emphasize the role of ultrasound as an objective tool in guiding therapy decisions. Our study offers valuable insights for optimizing treatment strategies in RA patients and improving their long-term outcomes.

Patterns of intrinsic capacity trajectory and onset of activities of daily living disability among community-dwelling older adults.

Global population ageing has brought about new challenges for elderly care. Exploring intrinsic capacity (IC) over time, which is designed as a composite measure of an individual's physical and mental capabilities, is essential for promoting healthy ageing and preventing dependency, such as that emerging from disability in activities of daily living (ADL). We aimed to identify and examine the differences between classes of IC trajectory and onset of ADL disability. We conducted an observational study using data from three waves (2011-15) of the China Health and Retirement Longitudinal Study, comprising 2609 participants with 6034 observations. IC was measured by five domains, including locomotion, cognition, psychological, sensory capacities, and vitality. We used joint latent class modelling to identify distinct classes with similar patterns of IC trajectory and onset of ADL disability, as well as to explore the variation in IC trajectory and predict five-year risks of ADL disability considering the heterogeneity in the elderly population. The average baseline IC score was 7.15 (range: 0-15). We observed that IC scores slowly decreased with age, with 17.25% of participants developing ADL disability. We identified three classes of IC, which could be described as moderate health (class 1: n = 1634, 62.63%), at-risk (class 2: n = 716, 27.44%; had the highest risk of ADL disability), and optimal health (class 3: n = 259, 9.93%; had the lowest baseline risk of ADL disability). The probability of being in the moderate health class was decreased the most by emotional problems (odds ratio (OR) = 0.219; P < 0.001). Having a self-rated poor standard of living substantially reduced the chances of moderate (OR = 0.308; P = 0.001) and optimal health (OR = 0.110; P < 0.001). Observing IC trajectories and the onset of ADL disability can stratify the elderly into heterogeneous groups, as well as provide data for implementing person-centred care plans to reverse the trend and delay the adverse outcomes in clinical practice.

Targeting chronic pain care to rural women veterans: A feasibility pilot.

For rural women veterans, significant barriers exist in accessing high-quality, multicomponent behavioral pain self-management interventions. As such, a telehealth behavioral pain self-management intervention designed specifically for rural-dwelling women veterans with chronic pain was piloted for this study. This mixed methods, single-arm preliminary study examined the feasibility and acceptability of this intervention and completed a responder analysis. Participants completed surveys before and 1-month following the intervention, and they completed a qualitative interview following the intervention. About one quarter (24%) of potentially eligible participants who were sent a letter about the study consented to participate (N = 44). All participants identified as female and were rural dwelling, with mean age of 56 years (range = 34-80), and the majority of the sample (81%) self-identified as White and non-Hispanic or Latino. Average baseline scores on the Pain, Enjoyment of Life, and General Activity three-item scale (PEG-3) measure indicated severe pain and functional interference (MPEG-3 total = 6.88, SD = 1.62). Of the 44 participants who consented, 70% completed the intervention. About half of treatment completers (47%, 14/30) were deemed responders, reporting ≥ 30% reduction on their PEG-3 total scores. On the Global Impression of Change scale, 87% reported improvement. Study completers indicated that the telehealth platform facilitated their engagement and that they perceived the intervention to be beneficial and credible. Qualitative data emphasized themes of connection with other women veterans who experienced chronic pain while perceiving a retained sense of individual identity. These preliminary data support feasibly of this intervention for rural-dwelling women veterans with chronic pain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

6602 Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort

Abstract Disclosure: M.D. Ettleson: None. G.C. Penna: Consulting Fee; Self; Ipsen, Bayer, Inc.. W. Wan: None. I.M. Bensenor: None. N. Laiteerapong: None. A.C. Bianco: Consulting Fee; Self; Abbvie. Classification of TSH Trajectories During Levothyroxine Treatment in the ELSA-Brasil Cohort Introduction: Hypothyroidism is a common endocrine disorder for which levothyroxine (LT4) serves as the primary treatment. Periods during which thyroid stimulating hormone (TSH) levels are outside the normal range have been associated with adverse cardiovascular outcomes, including mortality. In practice, serial TSH levels are measured over time to ensure therapeutic LT4 treatment is maintained. However, there is no measure of the quality of treatment maintenance over time. TSH trajectory classification represents a novel approach to define the adequacy of LT4 treatment for hypothyroidism over time utilizing multiple observation points. Methods: With longitudinal clinical data, including thyroid function from a large prospective study, we aimed to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over a 9 year study period with three observation points. Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to measure within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. Results: From the 621 LT4-treated study participants, the best-fit GMM approach identified four TSH trajectory classes, as defined by their relationship to the normal TSH range: 1) High-high normal TSH, 2) Normal TSH, 3) Normal-to-low TSH, and 4) Low-to-normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 mcg, p &amp;lt;0.001). There were no significant differences in CV health markers between the classes at baseline. At least one significant difference in CV markers occurred in all classes, highlighted by the low-to-normal class, in which total and HDL cholesterol, triglycerides, and A1c all increased significantly (p = 0.049, p &amp;lt;0.001, p &amp;lt;0.001, and p = 0.001, respectively). Medication utilization increased in all classes over the study period. Conclusion: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. In the future, more comprehensive datasets will allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes. Defining the adequacy of LT4 treatment using a longitudinal scope could allow clinicians to more accurately communicate treatment progress and identify patients at risk for adverse CV outcomes. Presentation: 6/3/2024

Effects of Oral Butyrate on Blood Pressure in Patients With Hypertension: A Randomized, Placebo-Controlled Trial.

The microbiota-derived short chain fatty acid butyrate has been shown to lower blood pressure (BP) in rodent studies. Nonetheless, the net effect of butyrate on hypertension in humans remains uncovered. In this study, for the first time, we aimed to determine the effect of oral butyrate on BP in patients with hypertension. We performed a double-blind randomized placebo-controlled trial including 23 patients with hypertension. Antihypertensive medication was discontinued for the duration of the study with a washout period of 4 weeks before starting the intervention. Participants received daily oral capsules containing either sodium butyrate or placebo with an equivalent dosage of sodium chloride for 4 weeks. The primary outcome was daytime 24-hour systolic BP. Differences between groups over time were assessed using linear mixed models (group-by-time interaction). Study participants (59.0±3.7 years; 56.5% female) had an average baseline office systolic BP of 143.5±14.6 mm Hg and diastolic BP of 93.0±8.3 mm Hg. Daytime 24-hour systolic and diastolic BP significantly increased over the intervention period in the butyrate compared with the placebo group, with an increase of +9.63 (95% CI, 2.02-17.20) mm Hg in daytime 24-hour systolic BP and +5.08 (95% CI, 1.34-8.78) mm Hg in diastolic BP over 4 weeks. Butyrate levels significantly increased in plasma, but not in feces, upon butyrate intake, underscoring its absorption. Four-week treatment with oral butyrate increased daytime systolic and diastolic BP in subjects with hypertension. Our findings implicate that butyrate does not have beneficial effects on human hypertension, which warrants caution in future butyrate intervention studies. URL: https://onderzoekmetmensen.nl/; Unique identifier: NL8924.

Cenobamate's Efficacy for Seizure Treatment in Tuberous Sclerosis Complex

BackgroundEpilepsy is prevalent, and seizure control is challenging in patients with tuberous sclerosis complex (TSC). Cenobamate (CBM) has proven efficacy in several studies; however, its benefit in the TSC population is not known. MethodsWe performed a retrospective review of patients with TSC who received adjunctive CBM for seizure treatments. We assessed treatment efficacy by comparing seizure frequencies three months before CBM (baseline) and those at 3-, 6-, 12-, and 18- month follow-ups. ResultsWe identified 70 patients with TSC receiving CBM and excluded 16 with insufficient data. Fifty-four patients aged 2 to 39 years, with an average baseline seizure of 66.1 ± 88.9 per month, were analyzed. Treatment retention rates at 3, 6, 12, and 18 months were 94.4%, 79.6%, 66.7%, 44.4%, and responder rates (proportions of patients who remained on treatment and had ≥50% seizure reduction) were 38.1%, 51.7%, 53.1%, and 59.1%, respectively. Seizure-free rates at these respective follow-ups were 7.1%, 13.8%, 6.3%, and 9.1%. For patients experiencing reduced seizures, the mean percentage of change ranged from 61.5% to 74.6%. Side effects were common (64.8%), particularly sedation (42.6%), behavioral disturbance (24.1%), and gastrointestinal disturbance (22.2%). ConclusionsMost patients in this study showed seizure reduction; however, the overall responder and seizure-free rates were lower than the literature, likely due to the unique underlying epileptogenesis in TSC and the challenges of tolerating CBM. The lower treatment retention rates signal areas for improvement in concurrent medication adjustment practices.

Raising the barcode: improving medication safety behaviours through a behavioural science-informed feedback intervention. A quality improvement project and difference-in-difference analysis

Barcode medication administration (BCMA) technology can improve patient safety by using scanning technology to ensure the right drug and dose are given to the right patient. Implementation can be challenging,...

Partial Residual Plots as an Integrated Model Diagnostic Tool in Model-Based Meta-Analysis.

The use of partial residual plots (PRPs) was explored as a model diagnostic tool in Model-based Meta-Analysis (MBMA). Mathematical derivations illustrating the concepts were followed by an MBMA example using publicly available literature data of anti-depressive treatments with fluoxetine and venlafaxine. An Emax dose-response model was identified for venlafaxine while a constant drug effect combining all dose levels vs. placebo was identified for fluoxetine. The larger the mean baseline Hamilton Depression Rating (HAMD) score, the larger the expected drug effect (P = 0.0122), based on the likelihood ratio test. Mean baseline HAMD score (range) was 25.4 (23.5, 29.4) and 20.8 (15, 26) while mean placebo change from baseline (range) was -9.02 (-12.2, -4.8) and - 6.22 (-10.9, -1.3) for venlafaxine and fluoxetine, respectively. Average baseline HAMD score appeared larger for venlafaxine compared to fluoxetine, albeit a wider range for fluoxetine. Placebo response seemed lower but also more variable in fluoxetine compared to venlafaxine studies. Observed data points tended to deviate from model predictions when the mean baseline HAMD and placebo response values associated with those data points differed substantially from the corresponding values used for the model prediction. Normalizing observed data addressed this, providing a "like-to-like" comparison with model predictions in PRP when assessing the effect of one covariate (dose) after normalizing for other covariates/effects (placebo response and mean baseline). PRPs provide a robust integrated diagnostic tool in MBMA that uses all data to show the correlation between response and any covariate while controlling for other covariates included in the model.

Orlando Veterans Affairs stratification tool for opioid risk mitigation (STORM) very high risk interdisciplinary team review: A brief report

BackgroundCompared to the general population, Veterans Health Administration (VHA) patients have higher rates of mental illness, chronic pain, and substance use disorders (SUD), conditions that increase risk for opioid-related adverse events. VHA developed the Stratification Tool for Opioid Risk Mitigation (STORM) and mandated case reviews by an interdisciplinary team (IDT) for patients identified as very high risk, a process implemented and led by clinical pharmacist practitioners at the Orlando Veterans Affairs Healthcare System (OVAHCS) in 2018. ObjectiveTo evaluate and describe the implementation and process for IDT reviews of patients identified as very high risk by the STORM clinical decision support tool at OVAHCS. MethodsA single center, retrospective, observational chart review was conducted. Veterans reviewed by the STORM IDT between January and September 2018 were reviewed for change in Morphine Equivalent Daily Dose (MEDD), naloxone, nonopioid analgesics, medications for SUD, benzodiazepines, engagement with clinical services (e.g., mental health, SUD, and pain clinic), and overdose or suicide attempts in the year prior versus the year after IDT review. The frequency of follow-up IDT reviews was evaluated. ResultsSeventeen patients were identified. Four were excluded due to nonopioid related death within 12 months after review. The average baseline MEDD was 82.2 mg (range 10–496 mg) and average 12 months after review was 7.5 mg (range 0 – 67.5 mg), a decrease of 74.7 mg, or 90.9% reduction. An increase in medications for SUD (3 patients; 23%), SUD engagement (3 to 6 patients), and urine drug tests was observed (79% increase). Benzodiazepine use decreased by 50%. ConclusionThis report provides insight on the IDT case review process at OVAHCS, a process that may vary widely across facilities. A reduction in MEDD, increase in SUD treatment, and improved risk mitigation was observed. The central role of clinical pharmacy and expanded process for continued follow-up warrants further study.

Matching-Adjusted Indirect Comparison of the Efficacy and Safety of Erdafitinib vs Enfortumab Vedotin in Patients with Locally Advanced Metastatic Urothelial Carcinoma.

Background: For patients with locally advanced or metastatic urothelial carcinoma (la/mUC), prognosis is poor and effective treatment options are limited. Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA for the treatment of adults with la/mUC harboring FGFR alterations whose disease progressed following at least 1 prior line of therapy, including a PD-1 or PD-L(1) inhibitor, based on the phase 3, randomized THOR trial (NCT03390504, Cohort 1). Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an anchored matching-adjusted indirect comparison (MAIC). Methods: An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician's choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. Individual patient data from THOR were adjusted to match published key eligibility criteria and average baseline characteristics of EV-301, such as Bellmunt risk score, liver or visceral metastases, primary site, among others. Erdafitinib was then indirectly compared with EV using the relative treatment effects for the reweighted THOR population and those published for EV-301. Results: After matching, the effective sample size for THOR was 126 patients. The MAIC-recalculated hazard ratio (95% credible interval) for erdafitinib vs EV was 0.92 (0.54, 1.57) for overall survival and 0.93 (0.55, 1.56) for progression-free survival, yielding Bayesian probabilities of erdafitinib being better than EV of 62.1% and 60.5%, respectively. For response outcomes, the MAIC-recalculated risk ratio was 1.49 (0.56, 3.90) for confirmed objective response rate and 2.89 (0.27, 30.33) for confirmed complete response with probabilities of 72.6% and 81.3% for erdafitinib being better than EV, respectively. For safety, MAIC-yielded risk ratios of 1.09 (0.99, 1.21) for any treatment-related adverse events, 0.86 (0.57, 1.28) for grade 3+ TRAEs, and 1.02 (0.98, 1.06) for any treatment-emergent adverse events. Conclusion: The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

Matching-Adjusted Indirect Comparison of the Efficacy and Safety of Erdafitinib vs Enfortumab Vedotin in Patients with Locally Advanced Metastatic Urothelial Carcinoma

Background: For patients with locally advanced or metastatic urothelial carcinoma (la/mUC), prognosis is poor and effective treatment options are limited. Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA for the treatment of adults with la/mUC harboring FGFR alterations whose disease progressed following at least 1 prior line of therapy, including a PD-1 or PD-L(1) inhibitor, based on the phase 3, randomized THOR trial (NCT03390504, Cohort 1). Objective: To compare the efficacy and safety of erdafitinib vs enfortumab vedotin-ejfv (EV) in the absence of head-to-head comparison via an anchored matching-adjusted indirect comparison (MAIC). Methods: An anchored MAIC was conducted according to the National Institute for Health and Care Excellence Decision Support Unit guidance, with physician’s choice of chemotherapy (docetaxel/paclitaxel and vinflunine) as the common comparator. Individual patient data from THOR were adjusted to match published key eligibility criteria and average baseline characteristics of EV-301, such as Bellmunt risk score, liver or visceral metastases, primary site, among others. Erdafitinib was then indirectly compared with EV using the relative treatment effects for the reweighted THOR population and those published for EV-301. Results: After matching, the effective sample size for THOR was 126 patients. The MAIC-recalculated hazard ratio (95% credible interval) for erdafitinib vs EV was 0.92 (0.54, 1.57) for overall survival and 0.93 (0.55, 1.56) for progression-free survival, yielding Bayesian probabilities of erdafitinib being better than EV of 62.1% and 60.5%, respectively. For response outcomes, the MAIC-recalculated risk ratio was 1.49 (0.56, 3.90) for confirmed objective response rate and 2.89 (0.27, 30.33) for confirmed complete response with probabilities of 72.6% and 81.3% for erdafitinib being better than EV, respectively. For safety, MAIC-yielded risk ratios of 1.09 (0.99, 1.21) for any treatment-related adverse events, 0.86 (0.57, 1.28) for grade 3+ TRAEs, and 1.02 (0.98, 1.06) for any treatment-emergent adverse events. Conclusion: The MAIC indicates comparable efficacy of erdafitinib vs EV for overall survival and progression-free survival, with erdafitinib showing a higher probability of achieving deep responses. While erdafitinib is associated with slightly more adverse events compared with EV, these events seem to be less severe.

Comparative efficacy of diroximel fumarate, ozanimod and interferon beta-1a for relapsing multiple sclerosis using matching-adjusted indirect comparisons.

Aim: Diroximel fumarate (DRF), ozanimod (OZA) and interferon beta-1a (IFN) are disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus OZA and IFN. We compared DRF versus OZA and DRF versus IFN using matching-adjusted indirect comparisons for efficacy outcomes, including annualized relapse rate (ARR), 12- and 24-week confirmed disability progression (CDP) and absence of gadolinium-enhancing (Gd+) T1 lesions and new/newly enlarging T2 lesions. Patients & methods: We used individual patient data from EVOLVE-MS-1 (NCT02634307), a 2-year, open-label, single-arm, phase III study of DRF (n=1057) and aggregate data from RADIANCE (NCT02047734), a 2-year, double-blind, phase III study that compared OZA 1mg once daily (n=433) and intramuscular IFN 30μg once weekly (n=441). To account for cross-trial differences, the EVOLVE-MS-1 population was restricted to those who met the inclusion/exclusion criteria for RADIANCE, then weighted to match the average baseline characteristics of RADIANCE. Results: After weighting, DRF and OZA had similar ARRs (0.18 and 0.17, respectively), with a rate difference (DRF vs OZA) of 0.01 (95% confidence interval [CI]: -0.04 to 0.06). DRF had a lower ARR than IFN (0.18 and 0.28, respectively), with a rate difference (DRF vs IFN) of -0.10 (95% CI: -0.16 to -0.04) after weighting. Outcomes for 12- and 24-week CDP favored DRF versus OZA; 12-week CDP favored DRF versus IFN, but there was not strong evidence favoring DRF over IFN for 24-week CDP. Compared with OZA and IFN, DRF had higher proportions of patients without Gd+ T1 lesions and patients without new/newly enlarging T2 lesions. Conclusion: Disability progression and radiological outcomes were favorable for DRF versus OZA, although no differences were observed in ARR. Clinical and radiological outcomes generally favored DRF versus IFN. These findings may be informative for patients and clinicians considering different treatment options for MS.

Preventing violence and enhancing mental health among clients of an invitro fertilization clinic in Jordan: results of a pre/post pilot test of the use of cognitive behavioral therapy

IntroductionInfertility increases women’s risk of intimate partner violence (IPV). Cognitive behavioral therapy (CBT) is commonly used to treat mental health problems among fertility treatment seeking patients. CBT has not been tested for its potential to reduce IPV in this population. We pilot test the use of CBT to prevent IPV and improve patients' mental health in a fertility clinic in Jordan.MethodsOf 38 eligible fertility-treatment seeking couples, 16 consented and underwent up to 11 CBT sessions (average = 9) over 3 months. Interviews at baseline and 16 weeks post intervention (endline) assessed IPV, quality of life, social support, coping, and fear of spouse. Wilcoxon signed-rank and McNemar’s tests were used to assess change in outcomes.ResultsAt baseline, women's rates of IPV, depression, and anxiety were 75%, 87.5%, and 75% respectively, whereas men's rates of depression and anxiety were each 80%. Average baseline post-traumatic stress disorder (PTSD) symptoms for men and women were 3.3 and 2.7 respectively out of 5. IPV decreased 25% after treatment, and women reported less spousal fear. For both men and women, depression, anxiety, and PTSD symptoms decreased and social support and fertility quality of life improved.ConclusionPsychosocial support should be standard of care for the treatment of infertility given the burden of mental health problems and IPV and the utility of CBT in this patient population. Co-design with couples is needed to identify strategies to bolster participation along with population-based interventions to combat the stigma of infertility and mental health service use and enhance women's status.

Detection of glaucoma progression on longitudinal series of en-face macular optical coherence tomography angiography images with a deep learning model

Background/aimsTo design a deep learning (DL) model for the detection of glaucoma progression with a longitudinal series of macular optical coherence tomography angiography (OCTA) images.Methods202 eyes of 134 patients with...