Outcomes and Costs in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving Front-Line Versus Delayed Caplacizumab: A US Hospital Database Study.

European real-world data indicate that front-line treatment with caplacizumab is associated with improved clinical outcomes compared with delayed caplacizumab treatment. The objective of the study was to describe the characteristics, treatment patterns, and outcomes in hospitalized patients with an immune-mediated thrombotic thrombocytopenic purpura (iTTP) episode treated with front-line versus delayed caplacizumab in the US. This retrospective cohort analysis of a US hospital database included adult patients (≥18 years) with an acute iTTP episode (a diagnosis of thrombotic microangiopathy and ≥1 therapeutic plasma exchange [TPE] procedure) from January 21, 2019, to February 28, 2021. Unadjusted baseline characteristics, treatment patterns, healthcare resource utilization, and costs were compared between patients who received front-line versus delayed (<2 vs ≥2 days after TPE initiation) caplacizumab treatment. Out of 39 patients, 16 (41.0%) received front-line and 23 (59.0%) received delayed treatment with caplacizumab. Baseline characteristics and symptoms were similar between the two groups. Patients who received front-line caplacizumab treatment had significantly fewer TPE administrations (median: 5.0 vs 12.0); and a significantly shorter hospital stay (median: 9.0 days vs 16.0 days) than patients receiving delayed caplacizumab therapy. Both of these were significantly lower in comparison of means (t-test P < .01). Median inpatient costs (inclusive of caplacizumab costs) were 54% higher in the delayed treated patients than in the front-line treated patients (median: $112 711 vs $73 318). TPE-specific cost was lower in the front-line treated cohort (median: $6 989 vs $10 917). In conclusion, front-line treatment with caplacizumab had shorter hospitalizations, lower healthcare resource utilization, and lower costs than delayed caplacizumab treatment after TPE therapy.

Impact of Treating Depression on Associated Comorbidities: A Systematic Literature Review.

Objective: To identify and summarize data that describe the impact of effectively treating major depressive disorder (MDD) on the severity or risk of serious comorbidities.Data Sources: MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several congresses were searched. Searches included terms related to MDD, randomized controlled trials (RCTs), and physical comorbidities and were restricted to English-language publications. Searches were conducted in November 2019 for the previous 2 years for conference proceedings; no date restriction was applied to the database searches.Study Selection: Included studies were RCTs or meta-analyses that assessed depression therapies. Studies were required to report a statistically significant improvement in depression scores as well as the concurrent impact on comorbidities. A total of 1,997 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: A total of 30 studies, including 24 RCTs (N = 6,333) and 6 meta/pooled analyses of RCTs, were included. Findings in several comorbidity categories were mixed; for example, in half (4 of 8) of the identified studies in people with cardiovascular disease and depression, individuals who received treatment leading to reduced depressive symptoms compared with a control arm also had a significantly decreased incidence of cardiovascular events or significantly improved cardiac disease symptom/severity scores compared with controls. Significant improvements in comorbid disease severity observed alongside improvements in depressive symptoms were also noted in studies of comorbid Parkinson's disease, multiple sclerosis, chronic pain and fibromyalgia, and chronic obstructive pulmonary disease.Conclusions: Effective treatment of MDD may lead to a reduction in the severity of certain serious comorbidities. These results highlight the importance of appropriate and timely treatment of MDD.

The impact of early remission on disease trajectory and patient outcomes in major depression disorder (MDD): A targeted literature review and microsimulation modeling approach based on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

BACKGROUND: While literature has suggested that the duration of a major depressive episode (MDE) may affect both symptomatic and functional outcomes in major depressive disorder (MDD), study designs are limited in their ability to isolate a causal relationship. METHODS: A targeted literature review was conducted using the MEDLINE database to assess whether there was an association between (1) shorter duration of an MDE, or (2) increased rapidity of symptom improvement, and MDD outcomes in adult patients. Given findings from the literature, we hypothesized that rapid symptom improvement could be associated with other longer-term clinical outcomes and used a previously-developed microsimulation model to test this hypothesis. The base case of the model replicated step-therapy treatment patterns, for 10,000 simulated patients, based on lines of therapy related to standard of care, observed remission rates, and observed time to relapse from the STAR*D study. In alternative scenario analyses, the step 1 remission rate was varied by +25 % and +50 % from the base case value to simulate the potential impact of improved earlier remission on disease trajectory and patient-level clinical outcomes. RESULTS: The literature review (N = 35 studies) suggests a statistically significant relationship between the duration of MDE or early symptom improvement and MDD outcomes. The microsimulation model corroborated these findings and demonstrated that increasing the rate of remission in step 1 results in patients experiencing decreased number of treatment steps, faster time to remission, decreased rate of reaching treatment-resistant depression, and delayed time to relapse. LIMITATIONS: Rates of relapse in STAR*D were deemed unreliable due to the high-loss of follow-up; rates of relapse for the MDD DTM were instead derived using parametric extrapolation methods (i.e., exponential, Weibull, log-logistic, Gaussian, log-normal, logistic). Adherence to treatment was assumed to be 100 %; however, non-adherence is expected to result in lower cumulative remission rates. CONCLUSION: Findings from the literature, coupled with quantification through a novel microsimulation model, demonstrate the potential impact of increased remission on disease trajectory and patient outcomes in MDD. While additional analyses with the model may be warranted to explore the impact of novel interventions on population health, including long-term outcomes (i.e., 5-year follow-up, lifetime follow-up), efforts by clinicians to increase remission early in the disease trajectory may improve long-term outcomes.

Impact of Major Depressive Disorder on Comorbidities: A Systematic Literature Review.

Objective: To summarize the breadth of data exploring the relationship between major depressive disorder (MDD) and both the incidence and the disease course of a range of comorbidities.Data Sources: The authors searched MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several prespecified congresses. Searches included terms related to MDD and several comorbidity categories, restricted to those published in the English language from 2005 onward.Study Selection: Eligibility criteria included observational studies within North America and Europe that examined the covariate-adjusted impact of MDD on the risk and/or severity of comorbidities. A total of 6,811 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: In total, 199 articles were included. Depression was significantly (P < .05) associated with an increased incidence of dementia and Alzheimer's disease as well as cognitive decline in individuals with existing disease; increased incidence and worsening of cardiovascular disease/events (although mixed results were found for stroke); worsening of metabolic syndrome; increased incidence of diabetes, particularly among men, and worsening of existing diabetes; increased incidence of obesity, particularly among women; increased incidence and worsening of certain autoimmune diseases; increased incidence and severity of HIV/AIDS; and increased incidence of drug abuse and severity of both alcohol and drug abuse.Conclusions: The presence of MDD was identified as a risk factor for both the development and the worsening of a range of comorbidities. These results highlight the importance of addressing depression early in its course and the need for integrating mental and general health care.

Humanistic and economic burden associated with depression in the United States: a cross-sectional survey analysis.

BACKGROUND: Depression (major depressive disorder [MDD]) affects the functioning of patients in many facets of life. Very few large-scale studies to date have compared health and economic related outcomes of those with versus without depression, and across various depression severity groups. We aimed to evaluate humanistic and economic burden in respondents with and without depression diagnosis, and across symptom severity groups. METHODS: Data from the 2017 US National Health and Wellness Survey (NHWS) were utilized. Of the adult respondents (N = 75,004), 59,786 were < 65 years old. Respondents not meeting eligibility criteria were excluded (e.g., those self-reporting bipolar disorder or experiencing depression in past 12 months but no depression diagnosis). Overall, data from 39,331 eligible respondents (aged 18-64 years) were analyzed; and comprised respondents 'with depression diagnosis' (n = 8853; self-reporting physician diagnosis of depression and experiencing depression in past 12 months) and respondents 'without depression diagnosis' (n = 30,478; no self-reported physician diagnosis of depression and not experiencing depression). Respondents with depression were further examined across depression severity based on Patient Health Questionnaire-9 (PHQ-9). Outcome measures included health-related quality-of-life (HRQoL; Medical Outcomes Study 36-item Short Form [SF-36v2]: mental and physical component summary [MCS and PCS]; Short-Form 6 Dimensions [SF-6D]; and EuroQol 5 Dimensions [EQ-5D]), work productivity and activity impairment (WPAI), and health resource utilization (HRU). Multivariate analysis was performed to examine group differences after adjusting covariates. RESULTS: Respondents with depression diagnosis reported significantly higher rates of diagnosed anxiety and sleep problems versus those without depression (for both; P < 0.001). Adjusted MCS, PCS, SF-6D, and EQ-5D scores were significantly lower in respondents with depression versus those without depression (all P < 0.001). Consistently, respondents with depression reported higher absenteeism, presenteeism, and overall WPAI, as well as greater number of provider visits, emergency room visits, and hospitalizations compared with those without depression (all P < 0.001). Further, burden of each outcome increased with an increase in disease severity. CONCLUSIONS: Diagnosed depression was associated with lower health-related quality-of-life and work productivity, and higher healthcare utilization than those without depression, and burden increased with an increase in symptom severity. The results show the burden of depression remains high even among those experiencing minimal symptoms.

Patient-reported health-related quality of life from a randomized, placebo-controlled phase 2 trial of zuranolone in adults with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD), a disabling, potentially life-threatening condition, negatively affects health-related quality of life (HRQoL). This secondary analysis aimed to understand the impact of the neuroactive steroid zuranolone on HRQoL using the Short Form-36v2 Health Survey (SF-36v2). METHODS: Adult patients with MDD and 17-item Hamilton Rating Scale for Depression total score ≥22 were randomized 1:1 to receive zuranolone 30 mg or placebo for 2 weeks, with 4 weeks follow-up. SF-36v2 scores were assessed at Day 15 across 8 domains (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and 2 summary scores (Physical and Mental Component), using a mixed-effects model for repeated measures. Correlations between SF-36v2 scores and clinician-reported efficacy endpoints were assessed using Pearson's correlation. RESULTS: Eighty-nine patients were treated with zuranolone 30 mg (n = 45) or placebo (n = 44). In zuranolone-treated patients, HRQoL improved across all SF-36v2 domains and summary scores at Day 15. Improvements exceeding established minimally important difference thresholds were observed in Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health scores. Improvements in General Health, Vitality, Mental Health, and Mental Component Summary were statistically significant versus placebo (p ≤ 0.025). Clinician-rated endpoints negatively correlated with SF-36v2 scores. LIMITATIONS: The small unipolar depression sample may not be representative of all US MDD patients. HRQoL measures could be impacted by factors unrelated to depression. CONCLUSIONS: Zuranolone-treated patients reported rapid and significant improvements in HRQoL versus placebo at Day 15. HRQoL improvements correlated with improvements in clinician-rated assessments. TRIAL REGISTRATION: clinicaltrials.gov:NCT03000530; https://clinicaltrials.gov/ct2/show/NCT03000530.

Improvement in clinical disease activity index when treatment selection is informed by the tumor necrosis factor-ɑ inhibitor molecular signature response classifier: analysis from the study to accelerate information of molecular signatures in rheumatoid arthritis.

BACKGROUND: A blood-based molecular signature response classifier (MSRC) predicts non-response to tumor necrosis factor-ɑ inhibitors (TNFi) in rheumatoid arthritis (RA). RESEARCH DESIGN AND METHODS: This is an interim analysis of data collected in the Study to Accelerate Information of Molecular Signatures (AIMS) in RA from patients who received the MSRC test between September 2020 and November 2021. Absolute changes in clinical disease activity index (CDAI) scores from baseline were evaluated at 12 weeks (n = 470) and 24 weeks (n = 274). RESULTS: Predicted TNFi non-responders who received a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) with an alternative mechanism of action (altMOA) experienced up to 1.8-fold greater improvements in CDAI scores than those treated with a TNFi (12 weeks: 12.2 vs 8.0; p-value = 0.083; 24 weeks: 14.2 vs 7.8 p-value = 0.009). In patients with a molecular signature of non-response to TNFi in high disease activity at baseline, this corresponded to 43.2% relative improvement in achieving a lower CDAI disease activity level when likely TNFi non-responders were treated with a non-TNFi therapy (38.9% vs 55.7%). Commensurate improvements in efficiency of spend are expected when TNFi are avoided in favor of altMOA. CONCLUSIONS: RA treatment selection informed by MSRC test results improves clinical outcomes in real-world care and offers improvements in efficiency of healthcare spending.

The Increasing Economic Burden with Additional Steps of Pharmacotherapy in Major Depressive Disorder.

OBJECTIVES: Major depressive disorder (MDD) is a common and serious disorder with significant impact on patients and families. The goal of this retrospective cohort study was to determine the economic burden among patients with MDD stratified by number of treatment lines needed for episode resolution. METHODS: Truven Health Analytics MarketScan® claims data were used to identify US patients (≥ 18 years) who were diagnosed with MDD and started on an antidepressant between 2013 and 2017. A generalized linear model estimated direct and employment-related costs for the first 12 months following initiation of treatment across cohorts with increasing number of lines of MDD pharmacotherapy. Analyses were adjusted for demographics and clinical factors. RESULTS: A total of 73,597 patients with MDD comprising the commercial (n = 66,459) and Medicare (n = 7138) populations met selection criteria. Patients who completed treatment for their episode with a single line of antidepressant had the lowest total adjusted direct costs (commercial $9975; Medicare $14,628) followed by those who completed with two lines (commercial $11,723; Medicare $15,526) and those treated with three or more lines of antidepressant regimens (commercial $21,259; Medicare $20,964). Patients who completed treatment with two lines as opposed to one incurred significantly higher direct costs (commercial +$1748, p < 0.0001; Medicare +$898, p = 0.0092). Patients who completed treatment with one line had the lowest employment-related costs compared to other groups. CONCLUSIONS: There was an increased economic burden associated with delay of episode resolution as early as the second line compared to the first line in MDD.

Number Needed to Treat and Number Needed to Harm analysis of the zuranolone phase 2 clinical trial results in major depressive disorder.

BACKGROUND: Zuranolone (SAGE-217) is a novel, investigational positive allosteric modulator of GABAA receptors being investigated in major depressive disorder (MDD). This analysis of phase 2 data quantified the benefit and risk of zuranolone (30mg) versus placebo and antidepressants in terms of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Rates of response, remission, and all-cause discontinuation for zuranolone and 11 antidepressant comparators were obtained from the zuranolone phase 2 clinical study (N=89) and a published network meta-analysis, respectively. An indirect treatment comparison was conducted using the Bucher method to compare zuranolone to standard-of-care. RESULTS: Zuranolone demonstrated greater benefit compared to placebo on Day 3 (NNT range for response=4-5, NNT for remission=10) and at Day 15 (NNT=3 for response and remission). Compared to SSRIs and SNRIs, zuranolone at Day 15 showed improved treatment response (NNT=4 [95% CI = 3; 16] and 5 [95% CI = 3; 25], respectively) and remission (NNT=4 [95% CI = 2; 13] and 4 [95% CI = 2; 18], respectively). This was accompanied by a reduction in all-cause discontinuation, with negative NNH values (-57 and -28), respectively. LIMITATIONS: Variations in study design across the included trials may limit the generalizability of results. CONCLUSIONS: With a small positive NNT as early as Day 3 indicating robust benefit and a negative NNH indicating reduced harm, this analysis based on a phase 2 study suggests that patients with MDD may benefit from the benefit-to-risk profile of zuranolone.

Impact of a multivariate serum-based proteomic test on physician treatment recommendations for advanced non-small-cell lung cancer.

OBJECTIVE: The VeriStrat 1 (VS) test is intended to help guide treatment decisions for patients with advanced non-small-cell lung cancer (NSCLC) without an EGFR-sensitizing mutation, classifying patients into two categories. Patients classified as VSGood have a favorable prognosis and significant clinical response to EGFR tyrosine kinase inhibitors (TKIs). Patients classified as VSPoor have a less favorable prognosis and exhibit no significant response to EGFR-TKIs. The objective of this paper is to assess the real-world impact of VS test results on physicians' treatment recommendations including referrals for best supportive care (BSC). METHODS: Between 1 January 2012 and 1 November 2016, physician respondents were asked to complete standardized questionnaires before and after receiving VS results in patients meeting criteria for the intended use of the VS test. This study evaluated three endpoints: whether physicians followed VS test results in making treatment recommendations, the extent to which tests results changed these treatment recommendations, and the patterns of care subsequent to VS testing. RESULTS: Of the tests ordered by 989 physicians, 2494 VS tests had completed treatment recommendation questionnaires both prior to and after testing. Prior to VS testing, physicians were considering treatment with EGFR-TKIs for 2250 patients (90%). The VS test classified 1950 patients as VSGood and 544 patients as VSPoor. For patients classified as VSPoor, physicians recommended BSC for 25% of patients and standard systemic treatments such as chemotherapies for 65% of patients. Consistent with previous publications, physicians recommended EGFR-TKI therapy for only 10% of VSPoor patients but for 89% of VSGood patients. Overall, physician's treatment recommendations were consistent with test results in 98% of cases. Availability of test results decreased ineffective treatment recommendations by 89% for VSPoor patients. CONCLUSIONS: Among physicians ordering VS, the test significantly influenced treatment recommendations for patients with NSCLC, reducing ineffective and expensive treatment at the end of life.

Isothermal titration calorimetry of supramolecular polymers.

A method to characterize the self-association of supramolecular polymers by isothermal titration calorimetry (ITC) has been designed. Association constants in the range 10(4)-10(6) dm(3) mol(-1) have been successfully determined from the heat exchange occurring when a supramolecular polymer solution is injected into a calorimetric cell containing pure solvent. Very good agreement with literature values has been obtained. Compared to other techniques (such as NMR or Fourier transform infrared spectroscopy), the use of ITC presents several advantages: (i) the enthalpy of association is obtained together with the association constant from the same experiment, (ii) the measurements can be performed in almost any solvent, and (iii) systems with higher association constants can be characterized.