Assessing the use of anti-PD1 monotherapy as adjuvant therapy and determinants of treatment choice in stage III cutaneous melanoma in the US.

BACKGROUND: The objective of this study was to describe real-world adjuvant therapy (AT) use by disease substage and assess determinants of treatment choice among patients with stage III melanoma. METHODS: This non-interventional retrospective study included survey responses and data from patient records provided by US medical oncologists. Survey responses, patient demographic/clinical characteristics, treatment utilization, and reasons for treatment were reported descriptively. The association between patient and disease characteristics and AT selection was assessed using logistic and multinomial regression models, overall and stratified by AJCC8 substage (IIIA vs. IIIB/C/D) and type of AT received (anti-PD1 monotherapy, BRAF/MEK, no AT), respectively. RESULTS: In total 152 medical oncologists completed the survey and reviewed the charts of 507 patients (168 stage IIIA; 339 stages IIIB/IIIC/IIID); 405 (79.9%) patients received AT (360/405 (88.9%) received anti-PD1 therapy; 45/405 (11.1%) received BRAF/MEK therapy). Physicians reported clinical guidelines (61.2%), treatment efficacy (37.5%), and ECOG performance status (31.6%) as drivers of AT prescription. Patient-level data confirmed that improving patient outcomes (79%) was the main reason for anti-PD1 prescription; expected limited treatment benefit (37%), patient refusal (36%), and toxicity concerns (30%) were reasons for not prescribing AT. In multivariable analyses stage IIIB/IIIC/IIID disease significantly increased the probability of receiving AT (odds ratio [OR] 1.74) and anti-PD1 therapy (OR 1.82); ECOG 2/3 and Medicaid/no insurance decreased the probability of AT receipt (OR 0.37 and 0.42, respectively) and anti-PD1 therapy (OR 0.41 and 0.42, respectively) among all patients and patients with stage IIIA disease. CONCLUSION: Most patients were given AT with a vast majority treated with an anti-PD1 therapy. Physician- and patient-level evidence confirmed the impact of disease substage on AT use, with stage IIIA patients, patients without adequate insurance coverage, and worse ECOG status having a lower probability of receiving AT.

Safety differences across androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer.

Approval of apalutamide, enzalutamide and darolutamide has transformed the treatment landscape and guideline recommendations for patients with nonmetastatic castration-resistant prostate cancer but now raises the issue of decision-making regarding treatment selection. In this perspective, we discuss the efficacy and safety of these second-generation androgen receptor inhibitors and propose that for patients with nonmetastatic castration-resistant prostate cancer, safety considerations for these treatments are especially important. We examine these considerations in the context of patient and caregiver preferences as well as patient clinical characteristics. We further posit that consideration of treatments' safety profiles should include not only the initial direct impacts from potential treatment-emergent adverse events and drug-drug interaction events, but also the full cascade of potentially avoidable healthcare complications.

Prostate cancer is one of the most common cancers in men. Because male hormones fuel the growth of prostate cancer cells, initial treatments generally focus on reducing these hormones to very low levels. Although these treatments are usually effective in controlling the cancer in the short term, over time, patients often stop responding to them. These patients need more advanced treatments to control their prostate cancer. For patients whose cancer has not spread to other body parts ('nonmetastatic castration-resistant prostate cancer'), more advanced treatment options were unavailable until recently, but during 2018­2019, three novel therapies became available. These new therapies have raised the question of how to choose a particular therapy when deciding on a patient's treatment regimen. Here we contend that patient safety is critical when deciding among these treatments, which are all similarly effective in terms of helping patients to live longer. We review the key differences of each drug's safety profile among these treatments. We assert that treatment selection should consider patients' preferences and clinical characteristics, as the latter can influence the potential for serious harm when treatment-related complications arise. Finally, treatment selection should consider the multiple after-effects that can occur following a treatment-related safety event.

Real-world effectiveness after initiating fremanezumab treatment in US patients with episodic and chronic migraine or difficult-to-treat migraine.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (mAb; IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for the preventive treatment of migraine in adults. The efficacy and safety of fremanezumab for migraine prevention have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world effectiveness data are needed to complement clinical trial data. This study assessed the effectiveness of fremanezumab across different subgroups of adult patients with episodic migraine (EM), chronic migraine (CM), or difficult-to-treat (DTT) migraine in real-world clinical settings. METHODS: This retrospective, panel-based online chart review used electronic case report forms. Patient inclusion criteria were a physician diagnosis of EM or CM; age ≥ 18 years at the time of first fremanezumab initiation; ≥ 1 dose of fremanezumab treatment; ≥ 1 follow-up visit since first initiation; and ≥ 2 measurements of monthly migraine days (MMD; with 1 within a month before or at first initiation and ≥ 1 after first initiation). Changes in MMD and monthly headache days were assessed during the follow-up period. These endpoints were evaluated in subgroups of patients by migraine type (EM/CM) and in subgroups with DTT migraine (diagnosis of medication overuse [MO], major depressive disorder [MDD], generalized anxiety disorder [GAD], or prior exposure to a different CGRP pathway-targeted mAb [CGRP mAb]). RESULTS: Data were collected from 421 clinicians and 1003 patients. Mean (percent) reductions from baseline in MMD at Month 6 were - 7.7 (77.0%) in EM patients, - 10.1 (68.7%) in CM patients, - 10.8 (80.6%) in the MO subgroup, - 9.9 (68.3%) in the MDD subgroup, - 9.5 (66.4%) in the GAD subgroup, and - 9.0 (68.7%) in the prior CGRP mAb exposure subgroup. Improvements in MDD or GAD severity were reported by 45.5% and 45.8% of patients with comorbid MDD or GAD, respectively. CONCLUSIONS: In this real-world study, fremanezumab demonstrated effectiveness for migraine regardless of migraine type or the presence of factors contributing to DTT migraine (MO, GAD, MDD, or prior exposure to a different CGRP mAb).

Real-world effectiveness of fremanezumab in migraine patients initiating treatment in the United States: results from a retrospective chart study.

BACKGROUND: The efficacy and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP) and is approved for the preventive treatment of migraine in adults, have been demonstrated in randomized, double-blind, placebo-controlled trials. Real-world data can further support those clinical trial data and demonstrate the full clinical benefits of fremanezumab. This chart review assessed the effectiveness of fremanezumab for improving clinical outcomes in adult patients with migraine treated according to real-world clinical practice. METHODS: This retrospective, panel-based, online physician chart review study used electronic case report forms with US physicians. Patient inclusion criteria were a physician diagnosis of migraine, fremanezumab treatment initiation at ≥ 18 years of age after US Food and Drug Administration approval, ≥ 1 dose of fremanezumab treatment, and ≥ 2 assessments of monthly migraine days (MMD; 1 within 30 days before treatment initiation and ≥ 1 after initiation). Changes from baseline in MMD, monthly headache days (MHD), and Migraine Disability Assessment (MIDAS) and 6-item Headache Impact Test (HIT-6) scores were assessed over 6 months. These endpoints were evaluated in the overall population and subgroups divided by dosing schedule and number of prior migraine preventive treatment failures. RESULTS: This study included data from 421 clinicians and 1003 patients. Mean age at fremanezumab initiation was 39.7 years, and most patients were female (75.8%). In the overall population, mean baseline MMD and MHD were 12.7 and 14.0, respectively. Mean (percent) reductions from baseline in MMD and MHD, respectively, were - 4.6 (36.2%) and - 4.7 (33.6%) at Month 1, - 6.7 (52.8%) and - 6.8 (48.6%) at Month 3, and - 9.2 (72.4%) and - 9.8 (70.0%) at Month 6. Mean (percent) reductions from baseline in MIDAS and HIT-6 scores also increased over the 6-month study period, from - 6.2 (21.6%) and - 8.4 (14.0%) at Month 1 to - 18.1 (63.1%) and - 16.2 (27.0%) at Month 6, respectively. Improvements in these outcomes over 6 months were observed across all evaluated subgroups. CONCLUSIONS: This real-world study demonstrated effectiveness of fremanezumab treatment for up to 6 months, irrespective of dosing regimen or number of prior migraine preventive treatment failures, reflecting ongoing, clinically meaningful improvements in patient outcomes.

Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer.

PURPOSE: No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons. MATERIALS AND METHODS: Individual patient data from the phase III ARAMIS trial (NPLACEBO=553; NDAROLUTAMIDE=943) were selected and reweighted to match the inclusion criteria and baseline characteristics published for the phase III SPARTAN (NPLACEBO=401; NAPALUTAMIDE=806) and PROSPER (NPLACEBO=468; NENZALUTAMIDE=933) trials. Only baseline factors consistently reported across trials were included as matching covariates. Both indirect comparisons matched on age, prostate specific antigen level and doubling time, Eastern Cooperative Oncology Group performance status, Gleason score, and bone-sparing agent use. Darolutamide vs apalutamide also matched on prior surgery and darolutamide vs enzalutamide also matched on region. Risk differences and odds ratios were calculated for adverse events and hazard ratios for metastasis-free survival. RESULTS: No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide. CONCLUSIONS: While metastasis-free survival did not differ across drugs in these cross-trial indirect comparisons, darolutamide showed a favorable safety and tolerability profile in prespecified adverse events vs apalutamide and enzalutamide. Consideration of these adverse events is important in clinical decision-making and treatment selection in nonmetastatic castration-resistant prostate cancer.

Hospital utilization rates following antipsychotic dose reduction in mood disorders: implications for treatment of tardive dyskinesia.

BACKGROUND: The relative benefits and risks of long-term maintenance treatment with antipsychotics have not been well studied in patients with bipolar disorder and major depressive disorder. For example, while antipsychotic dose reduction has been recommended in the management of serious side effects associated with antipsychotics, there is limited evidence on the impact of lowering doses on the course of underlying mood disorders. METHODS: This retrospective cohort study analyzed the impact of antipsychotic dose reduction in patients with bipolar disorder or major depressive disorder. Medical claims from six US states over a 6-year period were analyzed for patients with ≥10% or ≥ 30% reductions in antipsychotic dose (cases) and compared using survival analyses with matched controls receiving a stable dosage. Outcomes included hospitalizations for disease-specific mood disorders, other psychiatric disorders and all-cause emergency room visits, and claims for tardive dyskinesia. RESULTS: A total of 23,992 patients with bipolar disorder and 17,766 with major depressive disorder had a ≥ 10% dose reduction, while 19,308 and 14,728, respectively, had a ≥ 30% dose reduction. In multivariate analyses, cases with a ≥ 10% dose reduction had a significantly increased risk of disease-specific admission (bipolar disorder: hazard ratio [95% confidence interval], 1.22 [1.15-1.31]; major depressive disorder: 1.22 [1.11-1.34]), other psychiatric admission (bipolar disorder: 1.19 [1.13-1.24]; major depressive disorder: 1.17 [1.11-1.23]), all-cause admission (bipolar disorder: 1.17 [1.12-1.23]; major depressive disorder: 1.11 [1.05-1.16]), and all-cause emergency room visits (bipolar disorder: 1.09 [1.05-1.13]; major depressive disorder: 1.07 [1.02-1.11]) (all P <  0.01). Similar results were observed following an ≥30% dose reduction. Dose reduction was not associated with decreased claims for tardive dyskinesia. CONCLUSIONS: Patients with mood disorders who had antipsychotic dose reductions showed small but statistically significant increases in all-cause and mental health-related hospitalizations, which may lead to increased healthcare costs. These results highlight the need for additional long-term studies of the necessity and safety of maintenance antipsychotic treatment in mood disorders.

Risk assessment and prediction of TD incidence in psychiatric patients taking concomitant antipsychotics: a retrospective data analysis.

BACKGROUND: Tardive dyskinesia (TD) is a serious, often irreversible movement disorder caused by prolonged exposure to antipsychotics; identifying patients at risk for TD is critical to preventing it. Predictive models for the occurrence of TD can improve patient monitoring and inform implementation of counteractive interventions. This study aims to identify risk factors associated with TD and to develop a model using a retrospective data analysis to predict the incidence of TD among patients taking antipsychotic medications. METHODS: Adult patients with schizophrenia, major depressive disorder, or bipolar disorder taking oral antipsychotics were identified in a Medicaid claims database (covering six US states from 1997 to 2016) and divided into cohorts based on whether they developed TD within 1 year after the first observed claim for antipsychotics. Patient characteristics between cohorts were compared, and univariate Cox analyses were used to identify potential TD risk factors. A cross-validated version of the least absolute shrinkage and selection operator regression method was used to develop a parsimonious multivariable Cox proportional hazards model to predict diagnosis of TD. RESULTS: A total of 189,415 eligible patients were identified. Potential TD risk factors were identified based on the cohort analysis within a sample of 151,280 patients with at least 1 year of continuous eligibility. The prediction model had a clinically meaningful concordance of 70% and was well calibrated (P = 0.32 for Hosmer-Lemeshow goodness-of-fit test). Age (hazard ratio [HR] = 1.04, P < 0.001), diagnosis of schizophrenia (HR = 1.99, P < 0.001), antipsychotic dosage (up to 100 mg/day chlorpromazine equivalent; HR = 1.65, P < 0.01), and comorbid bipolar and related disorders (HR = 1.39, P < 0.01) were significantly associated with an increased risk of TD. Other potential risk factors included history of extrapyramidal symptoms (HR = 1.35), other movement disorders (parkinsonism, HR = 1.43; bradykinesia, HR = 1.44; tremors, HR = 2.12, and myoclonus, HR = 2.33), and diabetes (HR = 1.13). A modest reduction in the risk of TD was associated with the use of second-generation antipsychotics (HR = 0.85) versus first-generation drugs. CONCLUSIONS: This study identified factors associated with development of TD among patients taking antipsychotics. The prediction model described herein can enable physicians to better monitor patients at high risk for TD and recommend appropriate treatment plans to help maintain quality of life.

Dupilumab Versus Cyclosporine for the Treatment of Moderate-to-Severe Atopic Dermatitis in Adults: Indirect Comparison Using the Eczema Area and Severity Index.

Dupilumab is approved for uncontrolled moderate-to-severe atopic dermatitis (AD); cyclosporine is approved for severe AD for ≤ 1 year. The efficacy/effectiveness of these treat-ments was compared indirectly. Regression models used pooled patient-level data to estimate response (Eczema Area and Severity Index (EASI) EASI-50/EASI-75 at weeks 12-16 and 24-30) to dupilumab 300 mg every 2 weeks (CHRONOS [NCT02260986]) or cyclosporine (University Medical Center). Models were adjusted for sex, baseline EASI, and thymus and activation-regulated chemokine level. A total of 106 patients received dupilumab (+ topical cortico-steroids; + TCS), and 57 received cyclosporine (+ TCS). Among University Medical Center patients, estimated EASI-50 responders were, dupilumab vs. cyclosporine, 91% vs. 77% (p = 0.038; weeks 12-16), and 96% vs. 67% (p < 0.0001; weeks 24-30); EASI-75 responders were 78% vs. 56% (p = 0.016; weeks 12-16) and 80% vs. 47% (p <0.001; weeks 24-30). Among CHRONOS patients, estimated EASI-50 responders were 90% vs. 74% (p <0.038; weeks 12-16) and 92% vs. 53% (p < 0.0001; weeks 24-30); EASI-75 responders were 75% vs. 52% (p = 0.016; weeks 12-16) and 74% vs. 40% (p <0.001; weeks 24-30), respectively. These results suggest a higher relative efficacy of dupilumab vs. cyclosporine.

Systematic literature review of clinical trials of endocrine therapies for premenopausal women with metastatic HR+ HER2- breast cancer.

Several endocrine-based therapies have recently been evaluated as treatments for premenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC). We conducted a systematic review and assessed the feasibility of an indirect treatment comparison (ITC) to characterize the comparative efficacy of endocrine-based therapies in this setting. A systematic literature review (SLR) of Medline, EMBASE, Cochrane Library and key conferences was performed to identify randomized clinical trials (RCTs) satisfying the following criteria: (a) included pre/perimenopausal women with HR+/HER2- mBC, (b) included endocrine-based therapies, (c) reported efficacy, safety, or quality of life outcomes, and (d) was published in 2007 or later (when HER2 testing was standardized). The clinical and methodological similarities across trials were assessed to evaluate the feasibility of an ITC. Four RCTs (PALOMA-3, MONARCH-2, KCSG BR10-04 and MONALEESA-7) and eight regimens (palbociclib + fulvestrant + goserelin, fulvestrant + goserelin, abemaciclib + fulvestrant + gonadotropin-releasing hormone agonist [GnRHa], fulvestrant + GnRHa, anastrozole + goserelin, goserelin, ribociclib + NSAI/tamoxifen + goserelin and NSAI/tamoxifen + goserelin) were selected. MONALEESA-7 was the only phase 3 trial investigating endocrine-based therapies as first-line in only pre/perimenopausal women with HR+/HER2- mBC; the other three trials focused on the ET-failure setting and their pre/perimenopausal populations were relatively small. ITCs were methodologically unfeasible due to critical differences in treatment settings and lack of common comparators across trials. Therefore, we were not able to characterize the relative efficacy of the different endocrine-based therapies available in the premenopausal HR+/HER2- mBC setting. This systematic review provides a comprehensive assessment of the available trial evidence on the efficacy and safety of endocrine-based therapies for premenopausal women with HR+/HER2- mBC. Only four trials have reported relevant data in this setting, and MONALEESA-7 is currently the only trial focused on premenopausal HR+ HER2- mBC in the first-line setting.

Hospital utilization rates following antipsychotic dose reductions: implications for tardive dyskinesia.

BACKGROUND: Data are limited on the benefits and risks of dose reduction in managing side effects associated with antipsychotic treatment. As an example, antipsychotic dose reduction has been recommended in the management of tardive dyskinesia (TD), yet the benefits of lowering doses are not well studied. However, stable maintenance treatment is essential to prevent deterioration and relapse in schizophrenia. METHODS: A retrospective cohort study was conducted to analyze the healthcare burden of antipsychotic dose reduction in patients with schizophrenia. Medical claims from six US states spanning a six-year period were analyzed for ≥10% or ≥ 30% antipsychotic dose reductions compared with those from patients receiving a stable dose. Outcomes measured were inpatient admissions and emergency room (ER) visits for schizophrenia, all psychiatric disorders, and all causes, and TD claims. RESULTS: A total of 19,556 patients were identified with ≥10% dose reduction and 15,239 patients with ≥30% dose reduction. Following a ≥ 10% dose reduction, the risk of an all-cause inpatient admission increased (hazard ratio [HR] 1.17; 95% confidence interval [CI] 1.11, 1.23; P < 0.001), and the risk of an all-cause ER visit increased (HR 1.09; 95% CI 1.05, 1.14; P < 0.001) compared with controls. Patients with a ≥ 10% dose reduction had an increased risk of admission or ER visit for schizophrenia (HR 1.27; 95% CI 1.19, 1.36; P < 0.001) and for all psychiatric disorders (HR 1.16; 95% CI 1.10, 1.23; P < 0.001) compared with controls. A dose reduction of ≥30% also led to an increased risk of admission for all causes (HR 1.23; 95% CI 1.17, 1.31; P < 0.001), and for admission or ER visit for schizophrenia (HR 1.31; 95% CI 1.21, 1.41; P < 0.001) or for all psychiatric disorders (HR 1.21; 95% CI 1.14, 1.29; P < 0.001) compared with controls. Dose reductions had no significant effect on claims for TD. CONCLUSION: Patients with antipsychotic dose reductions showed significant increases in both all-cause and mental health-related hospitalizations, suggesting that antipsychotic dose reductions may lead to increased overall healthcare burden in some schizophrenia patients. This highlights the need for alternative strategies for the management of side effects, including TD, in schizophrenia patients that allow for maintaining effective antipsychotic treatment.

Comparative efficacy and safety of attention-deficit/hyperactivity disorder pharmacotherapies, including guanfacine extended release: a mixed treatment comparison.

This study compared the clinical efficacy and safety of attention-deficit/hyperactivity disorder (ADHD) pharmacotherapy in children and adolescents 6-17 years of age. A systematic literature review was conducted to identify randomized controlled trials (RCTs) of pharmacologic monotherapies among children and adolescents with ADHD. A Bayesian network meta-analysis was conducted to compare change in symptoms using the ADHD Rating Scale Version IV (ADHD-RS-IV), Clinical Global Impression-Improvement (CGI-I) response, all-cause discontinuation, and adverse event-related discontinuation. Thirty-six RCTs were included in the analysis. The mean (95% credible interval [CrI]) ADHD-RS-IV total score change from baseline (active minus placebo) was -14.98 (-17.14, -12.80) for lisdexamfetamine dimesylate (LDX), -9.33 (-11.63, -7.04) for methylphenidate (MPH) extended release, -8.68 (-10.63, -6.72) for guanfacine extended release (GXR), and -6.88 (-8.22, -5.49) for atomoxetine (ATX); data were unavailable for MPH immediate release. The relative risk (95% CrI) for CGI-I response (active versus placebo) was 2.56 (2.21, 2.91) for LDX, 2.13 (1.70, 2.54) for MPH extended release, 1.94 (1.59, 2.29) for GXR, 1.77 (1.31, 2.26) for ATX, and 1.62 (1.05, 2.17) for MPH immediate release. Among non-stimulant pharmacotherapies, GXR was more effective than ATX when comparing ADHD-RS-IV total score change (with a posterior probability of 93.91%) and CGI-I response (posterior probability 76.13%). This study found that LDX had greater efficacy than GXR, ATX, and MPH in the treatment of children and adolescents with ADHD. GXR had a high posterior probability of being more efficacious than ATX, although their CrIs overlapped.

Effect of adherence and insulin delivery system on clinical and economic outcomes among patients with type 2 diabetes initiating insulin treatment.

BACKGROUND: Adherence to insulin affects real-world health outcomes and may itself be affected by the choice of insulin delivery device (pen or vial/syringe). The choice of insulin delivery device may also have direct effects on effectiveness. OBJECTIVE: This study aimed to estimate the effects of insulin adherence and delivery device on real-world health outcomes. METHODS: This study included adults with type 2 diabetes mellitus initiating insulin, with continuous health plan insurance for 6 or more months before initiation (baseline) and 1 or more year after. Measured outcomes included glycosylated hemoglobin (Hb A1c) reduction, hospitalization rate, total health care costs, and pharmacy costs over 1 year of follow-up. Adherence (defined as having insulin fills sufficient for the entire quarter), pen or vial/syringe use, and disease-related patient characteristics were assessed in each quarter. To account for the time-varying relationship between adherence, patient characteristics, and outcomes, marginal structural generalized linear models were used to estimate the effect of adherence and device use. Mean outcomes were predicted for different combinations of adherence and device choice. RESULTS: Among the 13,428 patients (mean age 54 years; 46% women; baseline Hb A1c 9.3%), adherent pen users had greater reductions in Hb A1c (-0.35%; P = 0.045), lower hospitalization rates (-0.36; P < 0.01), and higher pharmacy costs ($2923; P < 0.01) than did nonadherent vial users, and similar total health care costs ($3906 lower; P = 0.1). Pen use and adherent vial use decreased hospitalization rate and increased pharmacy but not total costs. CONCLUSIONS: Adherence and pen use have beneficial effects on patients' real-world outcomes, with the most favorable effects attributable to adherent pen use.

Clinical Outcomes Before and After Prucalopride Treatment: An Observational Study in Patients With Chronic Idiopathic Constipation in the United States.

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan Commercial Claims and Encounters Database and the Medicare Supplemental Database (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification ( ICD-10-CM ) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, perianal/perirectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM , ICD-10 - Procedure Coding System , or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, and ≥65 years). RESULTS: This study included 690 patients: The mean (SD) patient age was 48.0 (14.7) years, and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P < 0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P < 0.001]; and nausea [22.6% vs 17.7%, P < 0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P < 0.001]; hemorrhoids [10.7% vs 7.0%, P < 0.05]; and rectal bleeding [4.1% vs 1.7%, P < 0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.

Comparison of outcomes on hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in anaemia associated with chronic kidney disease: network meta-analyses in dialysis and non-dialysis dependent populations.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are oral alternatives to current standard-of-care treatments for anaemia in chronic kidney disease (CKD). We conducted network meta-analyses to indirectly compare clinical outcomes for three HIF-PHIs in dialysis and non-dialysis populations with anaemia in CKD. Methods: The evidence base comprised phase III, randomised, controlled trials evaluating daprodustat, roxadustat, or vadadustat. Three outcomes were evaluated: efficacy [change from baseline in haemoglobin (Hgb)], cardiovascular safety [time to first major adverse cardiovascular event (MACE)] and quality of life [change from baseline in 36-Item Short Form Health Survey (SF-36) Vitality score]. Analyses were performed separately for all patients and for erythropoiesis-stimulating agent (ESA) non-users at baseline (non-dialysis population) or prevalent dialysis patients (dialysis population). Bayesian Markov Chain Monte Carlo methods with non-informative priors were used to estimate the posterior probability distribution and generate pairwise treatment comparisons. Point estimates (medians of posterior distributions) and 95% credible intervals (CrI) were calculated. Results: Seventeen trials were included. In non-dialysis patients, there were no clinically meaningful differences between the three HIF-PHIs with respect to Hgb change from baseline [all patients analysis (total n = 7907): daprodustat vs. roxadustat, 0.09 g/dL (95% CrI -0.14, 0.31); daprodustat vs. vadadustat, 0.09 g/dL (-0.04, 0.21); roxadustat vs. vadadustat, 0.00 g/dL (-0.22, 0.22)] or risk of MACE [all patients analysis (total n = 7959): daprodustat vs. roxadustat, hazard ratio (HR) 1.16 (95% CrI 0.76, 1.77); daprodustat vs. vadadustat, 0.88 (0.71, 1.09); roxadustat vs. vadadustat, 0.76 (0.50, 1.16)]. Daprodustat showed a greater increase in SF-36 Vitality compared with roxadustat [total n = 4880; treatment difference 4.70 points (95% CrI 0.08, 9.31)]. In dialysis patients, Hgb change from baseline was higher with daprodustat and roxadustat compared with vadadustat [all patients analysis (total n = 11 124): daprodustat, 0.34 g/dL (0.22, 0.45); roxadustat, 0.38 g/dL (0.27, 0.49)], while there were no clinically meaningful differences in the risk of MACE between the HIF-PHIs [all patients analysis (total n = 12 320): daprodustat vs. roxadustat, HR 0.89 (0.73, 1.08); daprodustat vs. vadadustat, HR 0.99 (0.82, 1.21); roxadustat vs. vadadustat, HR 1.12 (0.92, 1.37)]. Results were similar in analyses of ESA non-users and prevalent dialysis patients. Conclusions: In the setting of anaemia in CKD, indirect treatment comparisons suggest that daprodustat, roxadustat, and vadadustat are broadly clinically comparable in terms of efficacy and cardiovascular safety (precision was low for the latter), while daprodustat may be associated with reduction in fatigue to a greater extent than roxadustat.

Impact of Tardive Dyskinesia on Physical, Psychological, Social, and Professional Domains of Patient Lives: A Survey of Patients in the United States.

Objective: To assess the physical, psychological, social, and professional impact of tardive dyskinesia (TD) on patients in the United States.Methods: An online survey (April 2020-June 2021) to assess patient burden of TD was developed using targeted literature review and interviews with clinicians, patients, and caregivers. Survey participants (aged ≥ 18 years) with current diagnoses of TD and schizophrenia, bipolar disorder, or major depressive disorder rated the 7-day impact of TD on their physical, psychological, and social functioning via Likert scales (scored from 1 [least impact] to 5 [most impact]). Impact scores were calculated and summarized descriptively overall by self-reported disease severity and underlying disease. Participants also completed the Work Productivity and Activity Impairment Questionnaire and reported the impact of TD on their underlying psychiatric condition.Results: Overall, 269 patients (mean [SD] age = 40.6 years [9.9]; 74.7% employed) responded to the survey. Mean (SD) impact scores of 3.1 (0.9), 3.5 (1.0), and 3.2 (1.1) were reported in the physical, psychological, and social domains, respectively, and scores increased with reported TD symptom severity. Patients with underlying schizophrenia reported the highest burden for all domains. Patients reported 66.2% activity impairment because of TD. Employed patients (n = 193) indicated 29.1% absenteeism, 68.4% presenteeism, and 73.5% overall work impairment. Over one-third of patients reported skipping/reducing (48.4%) or stopping (39.3%) their antipsychotic medication and stopping visits to clinicians treating their underlying condition (35.7%) because of TD.Conclusion: TD imposes a substantial burden on patients' physical, psychological, social, and professional lives and impacts management of their underlying condition.

Impact of tardive dyskinesia on patients and caregivers: a survey of caregivers in the United States.

BACKGROUND: Tardive dyskinesia (TD) has a multidimensional impact on patients with TD and, as importantly, their caregivers. An online survey was developed and administered to assess patient and caregiver burden of TD. Survey participants were unpaid caregivers for patients with diagnoses of TD and schizophrenia, bipolar disorder, and/or major depressive disorder. Overall, 162 caregivers rated the 7-day impact of TD on the physical, psychological, and social functioning of patients and the impact of TD on these domains in their own lives and in their professional lives. RESULTS: Across physical, psychological, and social domains, most caregivers (82.7%) reported that TD had severe impact on the cared-for patients, and 23.5% reported severe impact of TD in their own lives. Caregivers experienced 46.4% activity impairment, and caregivers who were employed (n = 136) experienced 49.5% overall work impairment because of TD-related caregiving. CONCLUSIONS: These results suggest that TD imposes substantial burden for both caregivers and patients.

Predictors of persistence and adherence to deutetrabenazine among patients with Huntington disease or tardive dyskinesia.

Introduction: Deutetrabenazine is approved for treatment of Huntington disease (HD)-related chorea and tardive dyskinesia (TD) in adults. Factors associated with deutetrabenazine persistence and adherence are not well understood. Methods: Claims data from the Symphony Health Solutions Integrated Dataverse (2017-2019) were analyzed to identify real-world predictors of deutetrabenazine persistence and adherence in adults with HD or TD in the United States. Predictive models for persistence and adherence that considered patient demographics, payer type, comorbidities, treatment history, and health care resource use were developed. Results: In HD, use of anticonvulsants (HR = 2.00 [95% CI = 1.03, 3.85]; P < .05), lipid-lowering agents (2.22 [1.03, 4.76]; P < .05), and Medicaid versus Medicare insurance (2.27 [1.03, 5.00]; P < .05) predicted persistence, whereas only comorbid anxiety disorders predicted discontinuation (0.46 [0.23, 0.93]; P < .05). Of these patients, 62.5% were adherent at 6 months. Use of ≤2 treatments for chronic diseases (OR = 0.18 [95% CI = 0.04, 0.81]; P < .05) and Medicaid versus Medicare insurance (0.27 [0.09, 0.75]; P < .05) was associated with lower odds of adherence. In TD, use of lipid-lowering agents (HR = 4.76 [95% CI = 1.02, 20.00]; P < .05) predicted persistence, while comorbid schizoaffective disorder and/or schizophrenia (0.16 [0.14, 0.69]; P < .05) and sleep-wake disorders (0.18 [0.04, 0.82]; P < .05) predicted discontinuation. Of these patients, 46.7% were adherent at 6 months. Comorbid schizoaffective disorder and/or schizophrenia was associated with lower odds of adherence (OR = 0.26 [0.07, 0.91]; P < .05). Discussion: Identifying factors predictive of discontinuation and/or nonadherence to deutetrabenazine may facilitate the development of personalized support programs that seek to improve outcomes in patients with HD or TD.

An Experimental Study to Assess the Professional and Social Consequences of Tardive Dyskinesia.

OBJECTIVE: Antipsychotic medications may cause tardive dyskinesia (TD), an often-irreversible movement disorder characterized by involuntary movements that are typically stereotypic, choreiform, or dystonic and may impair quality of life. This study evaluated others' perceptions of abnormal TD movements in professional and social situations. METHODS: This was an experimental, randomized, blinded, digital survey in a general population sample. Participants were randomized 1:1 into a test or control group to view a video of a professional actor simulating TD movements or no TD movements prior to completing surveys on employment, dating, and friendship domains. Assessments for mild-to-moderate and moderate-to-severe TD movements were conducted separately. Authenticity of abnormal movements and Abnormal Involuntary Movement Scale (AIMS) scores were evaluated by physician experts. RESULTS: Surveys were completed by 2,400 participants each for mild-to-moderate and moderate-to-severe TD. In all domains, participants responded significantly less favorably to persons with TD movements (both mild-to-moderate and moderate-to-severe) than those without TD movements. Fewer participants in the test versus control group for mild-to-moderate and moderate-to-severe TD, respectively, considered the candidate as a potential employee (29.2% and 22.7% fewer), found him/her attractive (20.5% and 18.7% fewer), and were interested in becoming friends with him/her (12.3% and 16.5% fewer). CONCLUSION: Professional actors simulating TD movements were perceived more negatively than those without TD movements in employment, dating, and friendship domains. To our knowledge, this is the first randomized study to quantify professional and social stigma associated with TD movements that may reduce opportunities for gainful employment, marital status, and an effective support system.

Defining utility values for patients with tardive dyskinesia.

OBJECTIVE: To measure health state preferences and estimate utility values for tardive dyskinesia (TD) from the perspective of the US general population, accounting for factors affecting quality of life (QOL). METHODS: Participants from the general population were recruited and asked to watch and assess videos of professional actors simulating nine health states, including psychiatric disorders with/without TD and moderate-to-severe TD without any underlying disease. Time tradeoff (TTO) methods were used to elicit utility values, which ranged from -1 (worse than death) to +1 (perfect health) and represented individual preferences for avoiding specific health states associated with TD. Lower TTO utility values indicated individuals' willingness to give up more years of life to avoid living in each health state. RESULTS: Based on TTO responses (n = 157), mean ± standard deviation utility for TD alone was 0.59 ± 0.38. Mean utilities for schizophrenia with negative symptoms (without TD: 0.43; with TD: 0.29) and positive symptoms (without TD: 0.44; with TD: 0.30) were generally lower than those for bipolar disorder (without TD: 0.59; with TD: 0.46) and major depressive disorder (without TD: 0.60; with TD: 0.44). According to utility decrements associated with TD (0.13-0.16), respondents were willing to give up 1.3 to 1.6 years during a 10-year lifespan to avoid living with TD. CONCLUSIONS: Utility decrements for TD in this study were slightly larger than previously reported values, potentially due to incorporation of QOL and social consequences in TD health state descriptions. An important limitation of this analysis is that participants' willingness to trade future years of healthy life may not indicate actual willingness to accept the life decrement. These findings can be leveraged to improve cost-effectiveness analyses used to assess the value of treatments for TD.

Defining Utility Values for Chorea Health States in Patients with Huntington's Disease.

INTRODUCTION: Chorea is characterized by sudden, involuntary movements that interfere with quality of life (QOL). Utility values measure preferences for different health states and reflect societal perceived disease severity. To date, no studies have reported utility values specifically for Huntington's disease (HD) chorea. We estimated impact on QOL of HD chorea severity using utility values from the general population. METHODS: Participants were enrolled using computer-assisted telephone interviews. Participants read vignettes describing four health states for varying levels of chorea severity, with the same underlying HD severity. Time trade-off (TTO) methods were used to estimate utility values, which range from -1 (worse than death) to +1 (perfect health) and represent the number of years in an imperfect health state an individual is willing to give up to live in full health. TTO utilities were augmented with visual analog scale (VAS) participant responses. The primary outcome was HD chorea utility estimated by TTO. RESULTS: Mean ± SD TTO-derived utility values were 0.07 ± 0.52, 0.26 ± 0.50, 0.48 ± 0.47, and 0.64 ± 0.41 for severe, moderate/severe, moderate/mild, and mild chorea severity, respectively. Differences between each health state and its adjacent less severe health state were statistically significant (all P < 0.0001). Respondents were willing to give up 3.6, 5.2, 7.4, and 9.3 years during a 10-year life span to avoid living with mild, mild/moderate, moderate/severe, and severe chorea, respectively. VAS and TTO results were consistent. CONCLUSIONS: Significant decreases in utility values were seen as HD chorea severity increased. These data can be leveraged for cost-effectiveness modeling to better understand the value of treatments for chorea.