Comparative efficacy, quality of life, safety, and tolerability of atogepant and rimegepant in migraine prevention: A matching-adjusted indirect comparison analysis.

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. RESULTS: There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. CONCLUSION: In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

Impact of headache frequency and preventive treatment failure on quality of life, disability, and direct and indirect costs among individuals with episodic migraine in the United States.

OBJECTIVE: To evaluate unmet needs among individuals with episodic migraine (EM) in the United States (US). BACKGROUND: Data are limited on the impact of headache frequency (HF) and preventive treatment failure (TF) on the burden of migraine in the US. METHODS: A retrospective, cross-sectional analysis of 2019 National Health and Wellness Survey (NHWS) data was conducted from an opt-in online survey that identified respondents (aged ≥18 years) in the US with self-reported physician-diagnosed migraine. Participants were stratified by HF (low: 0-3 days/month; moderate-to-high: 4-14 days/month) and prior preventive TF (preventive naive; 0-1 TF; ≥2 TFs). Comparisons were conducted between preventive TF groups using multivariable regression models controlling for patient demographic and health characteristics. RESULTS: Among individuals with moderate-to-high frequency EM, the NHWS identified 397 with ≥2 TFs, 334 with 0-1 TF, and 356 as preventive naive. The 36-item Short-Form Health Survey (version 2) Physical Component Summary scores were significantly lower among those with ≥2 TFs, at a mean (standard error [SE]) of 41.4 [0.8] versus the preventive-naive 46.8 [0.9] and 0-1 TF 44.5 [0.9] groups; p < 0.001 for both). Migraine Disability Assessment Scale scores were significantly higher in the ≥2 TFs, at a mean (SE) of 37.7 (3.9) versus preventive-naive 26.8 (2.9) (p < 0.001) and 0-1 TF 30.1 (3.3) (p = 0.011) groups. The percentages of time that respondents experienced absenteeism (mean [SE] 21.6% [5.5%] vs. 13.4% [3.6%]; p = 0.022), presenteeism (mean [SE] 55.0% [8.3%] vs. 40.8% [6.5%]; p = 0.015), overall work impairment (mean [SE] 59.4% [5.6%] vs. 45.0% [4.4%]; p < 0.001), and activity impairment (mean [SE] 56.8% [1.0%] vs. 44.4% [0.9%]; p < 0.001) were significantly higher in the ≥2 TFs versus preventive-naive group. Emergency department visits (preventive-naive, p = 0.006; 0-1 TF, p = 0.008) and hospitalizations (p < 0.001 both) in the past 6 months were significantly higher in the ≥2 TFs group. Direct and indirect costs were significantly higher in the ≥2 TFs (mean [SE] $24,026 [3460]; $22,074 [20]) versus 0-1 TF ($10,897 [1636]; $17,965 [17]) and preventive-naive ($11,497 [1715]; $17,167 [17]) groups (p < 0.001 for all). Results were similar in the low-frequency EM group. CONCLUSIONS: In this NHWS analysis, individuals with more prior preventive TFs experienced significantly higher humanistic and economic burden regardless of HF.

Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. METHODS: In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score. RESULTS: Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52. CONCLUSION: Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact.Trial Registration: NCT03700320.

Impact of headache frequency and preventive medication failure on quality of life, functioning, and costs among individuals with migraine across several European countries: need for effective preventive treatment.

BACKGROUND: Data are limited regarding the combined impact of headache frequency and failure of preventive medication (efficacy and/or tolerability) on the humanistic/economic burden of migraine. METHODS: A retrospective, cross-sectional analysis of 2020 National Health and Wellness Survey (NHWS) data was conducted. An opt-in online survey identified adults in France, Germany, Italy, Spain, and United Kingdom with self-reported physician-diagnosed migraine. Participants with ≥ 4 monthly headache days (MHDs) were stratified by prior preventive medication use/failure (preventive naive; 0-1 failure; ≥ 2 failures). Quality-of-life and economic outcomes were compared among groups using generalized linear modeling. RESULTS: Among individuals with ≥ 4 MHDs (n = 1106), the NHWS identified 298 (27%) with ≥ 2 failures, 308 (28%) with 0-1 failure, and 500 (45%) as preventive naive. Individuals with ≥ 2 failures versus preventive-naive individuals had significantly lower scores on the 12-Item Short Form Survey Physical Component Summary (42.2 vs 44.1; P < 0.005), numerically higher scores on the Mental Component Summary (39.5 vs 38.5; P = 0.145), significantly higher scores on the Migraine Disability Assessment (39.1 vs 34.0; P < 0.05), and significantly higher prevalence of depression symptoms (62% vs 47%; P < 0.001) and anxiety symptoms (42% vs 31%; P < 0.01). The ≥ 2 failures group versus the preventive-naive group also had significantly more functional impairment as assessed by mean numbers of migraine-specific missed work days (7.8 vs 4.3) and household activities days (14.3 vs 10.6) in the past 6 months (P < 0.001) as well as the prevalence of absenteeism (19% vs 13%), overall work impairment (53% vs 42%), and activity impairment (53% vs 47%) (all P < 0.05). Emergency department visits (0.7 vs 0.5; P = 0.001) and hospitalizations (0.5 vs 0.3; P < 0.001) in the past 6 months were significantly higher in the ≥ 2 failures group versus the preventive-naive group, while indirect costs (€13,720 vs €11,282) and the proportion of individuals with non-adherence during the past 7 days (73% vs 64%) were numerically higher. CONCLUSIONS: Increased burden, quality-of-life impairment, and functional impairment exist among individuals with migraine experiencing ≥ 4 MHDs and more treatment failures. While cause and directionality cannot be determined, these results suggest the need for effective preventive migraine treatments.

Development and validation of a novel patient-reported outcome measure in people with episodic migraine and chronic migraine: The Activity Impairment in Migraine Diary.

OBJECTIVE: To evaluate the content validity and psychometric properties of the Activity Impairment in Migraine Diary (AIM-D). BACKGROUND: Measuring treatment effects on migraine impairment requires a psychometrically sound patient-reported outcome (PRO) measure developed consistent with U.S. Food and Drug Administration guidance. METHODS: The AIM-D was created from concepts that emerged during qualitative interviews with five clinicians experienced in treating migraine and concept elicitation (CE) interviews with 40 adults with episodic migraine (EM) or chronic migraine (CM). The initial version was refined based on three waves of cognitive interviews with 38 adults with EM or CM and input from a panel of clinical and measurement experts. The AIM-D was psychometrically evaluated using data from 316 adults with EM or CM who participated in a 13-week prospective observational study. Study participants completed PRO assessments including the AIM-D and a daily headache diary. Exploratory and confirmatory factor analysis were used to determine the factor structure. The reliability, validity, and responsiveness of the AIM-D were assessed. Additional PRO measures including the Patient Global Impression - Severity (PGI-S), Migraine Specific Quality of Life Questionnaire, Version 2.1 Role Function-Restrictive domain, and Headache Impact Test were used for psychometric evaluation of the AIM-D. RESULTS: Based on CE interviews with adults with migraine and input from an expert panel, activity impairment was identified as the target in the preliminary conceptual framework, which had two domains: performance of daily activities (PDAs) and physical impairment (PI). Revision of the draft AIM-D through multiple rounds of cognitive interviews and expert panel meetings resulted in a content valid 11-item version. Exploratory factor analysis supported both one- and two-domain structures for the AIM-D, which were further supported by confirmatory factor analysis (factor loadings all >0.90). The AIM-D domains (PDA and PI) and total score showed high internal consistency reliability (Cronbach's alpha 0.95-0.97), acceptable test-retest reliability for weekly average scores (intraclass correlation coefficient >0.60 for participants with no change in PGI-S between baseline and week 2), and good convergent and known-groups validity. There was evidence of responsiveness based on changes in PGI-S score and monthly migraine days. CONCLUSION: The AIM-D is a content valid and psychometrically sound measure designed to evaluate activity impairment and is suitable for use in clinical trials of preventive treatments for EM or CM.

Healthcare utilization and costs for patients initiating Dabigatran or Warfarin.

BACKGROUND: Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. METHODS: A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. RESULTS: A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P < 0.01), office visits (21.43 vs. 29.41; P < 0.01), and outpatient visits (10.86 vs. 22.02; P < 0.01) were lower among dabigatran compared to warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P < 0.001); however, mean medical costs PPPM ($1912 vs. $1956, P = 0.55) and mean total costs PPPM ($2381 vs. $2183, P = 0.10) were not significantly different compared to warfarin users. CONCLUSIONS: Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all-cause costs.

An item-level response shift study on the change of health state with the rating of asthma-specific quality of life: a report from the PROMIS(®) Pediatric Asthma Study.

PURPOSE: To examine item-level response shift associated with the change in asthma-related health state (i.e., change in asthma control status and global rating of change (GRC) in breathing problems). METHODS: Study sample comprised 238 asthmatic children who were between 8 and 17.9 years and completed the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) symptoms, emotion function, and activity limitation domains at baseline and a follow-up assessment. Structural equation modeling was implemented to assess item-level response shift associated with the change in asthma-related health state with the adjustment for the influence of confounding variables. The magnitude of item-level response shift and its influence on the change of domain scores was estimated using Cohen's effect sizes. RESULTS: We found no instances of item-level response shift. However, two items were identified with measurement bias related to GRC due to breathing problems. Specifically, asthmatic children with better/about the same GRC due to breathing problems reported lower scores for one item in the emotional domain at follow-up compared to those with deteriorated GRC due to breathing problems. In addition, asthmatic children with better/about the same GRC due to breathing problems reported better scores for another item in the symptom domain at baseline compared to those with deteriorated GRC due to breathing problems. The impact of measurement bias was small and did not bias the change of domain scores over time. CONCLUSIONS: No item-level response shift, but two instances of measurement bias, appears in asthmatic children. However, the impact of these measurement issues is negligible.

The relationship between four health-related quality-of-life indicators and use of mammography and Pap test screening in US women.

PURPOSE: Limited evidence is available to explain the role of four components of health-related quality of life (HRQoL) on breast and cervical cancer screening. The objective of this study was to determine the relationship between four HRQoL aspects and use of mammography and Pap test screening in US women. METHODS: Data were obtained from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). The outcome variables were receiving mammogram <2 versus ≥2 years in women aged 50-74 years, and receiving Pap test <3 versus ≥3 years in women aged 18-64 years. Eight logistic regression models were conducted to test the role of four HRQoL aspects (general health status, physical HRQoL, mental HRQoL, and activity limitation) on the two screening variables, after adjusting for covariates. Statistical analysis accounted for the complex sampling design of the BRFSS, and the a priori alpha error was set at p ≤ 0.05. RESULTS: Among respondents, approximately 74 and 78 % of the women received mammography and Pap test, respectively. Three HRQoL aspects (general health status, physical HRQoL, and activity limitation) were significantly associated with mammography use (all p values < 0.05), whereas two HRQoL aspects (general health status and physical HRQoL) were significantly associated with Pap test (p values ≤ 0.05). All significant relationships demonstrated higher cancer screening rates among individuals with better HRQoL. CONCLUSIONS: HRQoL is an important factor associated with use of mammography and Pap test. Future studies should explore the mechanisms associated with an individual's HRQoL and use HRQoL assessment as an avenue to influence adherence to use of mammography and Pap tests.

Adolescent body weight and health-related quality of life rated by adolescents and parents: the issue of measurement bias.

BACKGROUND: Evidence is sparse about whether body weight categories in adolescents are associated with differences in pediatric HRQoL rated by adolescents and parents. Additionally, it is unknown whether HRQoL rated by individuals with different body mass index (BMI) weight categories is psychometrically comparable. This study aimed to assess whether difference in pediatric HRQoL rated by adolescents and their parents was explained by BMI weight status, and to test measurement properties of HRQoL items related to weight categories using differential item functioning (DIF) methodology. DIF refers to the situation when the individuals across subgroups rate an item differently (e.g., item score three by one subgroup and four by another) given the same underlying construct. METHODS: A cross-sectional study utilizing a sample of parents (n = 323) and their adolescents aged 15-18 years old (n = 323) who enrolled in Florida's Medicaid. Adolescent self-reports and parent proxy-reports of the Pediatric Quality of Life Inventory was adopted to measure pediatric HRQoL. We classified body weight categories as normal weight, overweight, and obesity. A Multiple Indicator Multiple Cause (MIMIC) method was used to assess DIF associated with BMI weight status, especially testing the disparity in the parameters of different weight categories (reference: lower weight category) associated with a response to a HRQoL item conditioning on the same underlying HRQoL. DIF analyses were conducted by adolescent self-reports and parent proxy-reports. RESULTS: Parents reported lower pediatric HRQoL across all domains than adolescents did. Excess body weight (combined overweight and obese) was significantly associated with a greater discrepancy in the rating of emotional and total functioning between adolescents and parents (p < 0.05). DIF associated with BMI weight categories was identified by two items in adolescent self-reports and five items in parent proxy-reports. CONCLUSIONS: Adolescents' BMI weight categories significantly contribute to a difference in the rating of pediatric HRQoL by adolescents and parents.

Detangling the Threads of Hairy Cell Leukemia, Beyond the Morphology and Into the Molecular.

Hairy cell leukemia (HCL) makes up 2% of leukemias in the United States and encompasses great molecular heterogeneity. The standard treatment paradigm involves purine nucleoside analogues in the upfront setting with high complete response rate to initial therapy but frequent relapses. There is an increasing role for BRAF inhibitors, with or without rituximab, in refractory and even in untreated patients. The response to purine analogues in HCL variant cases, otherwise classified as splenic lymphoma with prominent nucleolus in the 5th WHO edition classification, is less robust. Several antibodies, small molecular inhibitors, and combination regimens have been explored in HCL but data is frequently limited by case reports or small case series. Here we review available treatment options including their efficacy and safety profiles. We also explore investigational agents and potential future targets. The goal is to present a comprehensive therapeutic review of this rare disease entity and outline the ever increasing and novel therapeutic management options which interrupt key pathways in the pathogenesis of this malignancy.

Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial.

BACKGROUND AND OBJECTIVES: Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse. METHODS: This subgroup analysis of the phase 3, 12-week, randomized, double-blind, placebo-controlled PROGRESS trial evaluated adults with a ≥1-year history of CM, ≥15 monthly headache days (MHDs), and ≥8 monthly migraine days (MMDs) during the 4-week baseline period. Participants were randomized (1:1:1) to placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks and were analyzed by acute medication overuse status (triptans/ergots for ≥10 days per month, simple analgesics for ≥15 days per month, or combinations of triptans/ergots/simple analgesics for ≥10 days per month). Outcomes included change from baseline in mean MMDs, MHDs, and monthly acute medication use days; ≥50% reduction in mean MMDs across 12 weeks; and patient-reported outcome (PRO) measures. RESULTS: Of 755 participants in the modified intent-to-treat population, 500 (66.2%) met baseline acute medication overuse criteria (placebo, n = 169 [68.7%]; atogepant 30 mg BID, n = 161 [63.6%]; atogepant 60 mg QD, n = 170 [66.4%]). The least squares mean difference (LSMD) (95% CI) from placebo in MMDs was -2.7 (-4.0 to -1.4) with atogepant 30 mg BID and -1.9 (-3.2 to -0.6) with atogepant 60 mg QD. Mean MHDs (LSMD [95% CI] -2.8 [-4.0 to -1.5] and -2.1 [-3.3 to -0.8]) and mean acute medication use days (LSMD [95% CI] -2.8 [-4.1 to -1.6] and -2.6 [-3.9 to -1.3]) were reduced and a higher proportion of participants achieved ≥50% reduction in MMDs (odds ratio [95% CI] 2.5 [1.5-4.0] and 2.3 [1.4-3.7]) with atogepant 30 mg BID and atogepant 60 mg QD. There was a 52.1%-61.9% reduction in the proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks. Atogepant improved PRO measures. Similar results were observed in the subgroup without acute medication overuse. DISCUSSION: Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03855137. Submitted: February 25, 2019; first patient enrolled: March 11, 2019. clinicaltrials.gov/ct2/show/NCT03855137. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that atogepant reduces mean MMDs, MHDs, and monthly acute medication use days in adult patients with or without medication overuse.

Exploring factors influencing asthma control and asthma-specific health-related quality of life among children.

BACKGROUND: Little is known about factors contributing to children's asthma control status and health-related quality of life (HRQoL). The study objectives were to assess the relationship between asthma control and asthma-specific HRQoL in asthmatic children, and to examine the extent to which parental health literacy, perceived self-efficacy with patient-physician interaction, and satisfaction with shared decision-making (SDM) contribute to children's asthma control and asthma-specific HRQoL. METHODS: This cross-sectional study utilized data collected from a sample of asthmatic children (n = 160) aged 8-17 years and their parents (n = 160) who visited a university medical center. Asthma-specific HRQoL was self-reported by children using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Asthma Impact Scale. Satisfaction with SDM, perceived self-efficacy with patient-physician interaction, parental health literacy, and asthma control were reported by parents using standardized measures. Structural equation modeling (SEM) was performed to test the hypothesized pathways. RESULTS: Path analysis revealed that children with better asthma control reported higher asthma-specific HRQoL (ß = 0.4, P < 0.001). Parents with higher health literacy and greater perceived self-efficacy with patient-physician interactions were associated with higher satisfaction with SDM (ß = 0.38, P < 0.05; ß = 0.58, P < 0.001, respectively). Greater satisfaction with SDM was in turn associated with better asthma control (ß = -0.26, P < 0.01). CONCLUSION: Children's asthma control status influenced their asthma-specific HRQoL. However, parental factors such as perceived self-efficacy with patient-physician interaction and satisfaction with shared decision-making indirectly influenced children's asthma control status and asthma-specific HRQoL.

The relationships between fatigue, quality of life, and family impact among children with special health care needs.

OBJECTIVE: To examine the relationships among pediatric fatigue, health-related quality of life (HRQOL), and family impact among children with special health care needs (CSHCNs), specifically whether HRQOL mediates the influence of fatigue on family impact. METHODS: 266 caregivers of CSHCNs were studied. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, Pediatric Quality of Life Inventory Generic Scale, and Impact on Family Scale were used to measure fatigue, HRQOL, and family impact, respectively. Linear regressions were used to analyze the designated relationships; path analyses were performed to quantify the mediating effects of HRQOL on fatigue-family impact relationship. RESULTS: Although greater fatigue was associated with family impact (p < .05), the association was not significant after accounting for HRQOL. Path analyses indicated the direct effect of fatigue on family impact was not significant (p > .05), whereas physical and emotional functioning significantly mediated the fatigue-family impact relationship (p < .001). CONCLUSION: Fatigue is related to family impact among CSHCNs, acting through the impairment in HRQOL.

Assessment of response shift using two structural equation modeling techniques.

OBJECTIVE: To identify response shift using two structural equation modeling (SEM) techniques. STUDY DESIGN AND SETTING: Hypertensive patients (n = 909) with coronary artery disease (CAD) completed SF-36 surveys at both baseline and 1-year follow-up. Response shift was identified using Oort and Schmitt SEM techniques. The type of response shift linked to changes in various parameters of the SEM measurement model is defined differently for both SEM approaches. Effect sizes were calculated for the impact of response shift on the change of SF-36 domain scores when using the Oort approach. RESULTS: Both Oort and Schmitt SEM approaches identified response shift only in the SF-36 physical functioning (PF) scale. The effect size of recalibration on the change of PF domain scores when using the Oort approach was -0.12. CONCLUSION: This study showed that hypertensive patients with CAD experienced a response shift over a 1-year period. Both the SEM approaches identified response shift (uniform recalibration using the Oort approach and recalibration using the Schmitt approach); however, both approaches use different parameters to define and test response shift. We found that either the variation in analytic methods or the sample used may influence the identification and type of response shift.

Dabigatran-dronedarone interaction in a spontaneous reporting system.

OBJECTIVES: To investigate the risk of bleeding events associated with concurrent administration of dabigatran-dronedarone compared with dabigatran standalone therapy using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and to identify the characteristics of patients with bleeding events associated with concurrent use of dabigatran and dronedarone. DESIGN: Retrospective data mining analysis. SETTING: United States, from the dabigatran approval date (October 19, 2010) through the fourth quarter of 2011. PATIENTS: Cases from FAERS with bleeding events (combined in a single term based on adverse event reports such as hemorrhage and rectal hemorrhage) as the adverse event. INTERVENTION: Cases listing concomitant use of the terms Pradaxa, dabigatran, or dabigatran etexilate with Multaq or dronedarone as the suspect drug from FAERS and cases listing dabigatran and dronedarone as standalone therapies were extracted for analysis. MAIN OUTCOME MEASURE: Risk of bleeding among those using dabigatran-dronedarone concomitantly compared with those using dabigatran standalone therapy. RESULTS: 108 dabigatran-dronedarone interaction reports and 14,913 reports concerning bleeding events were extracted from FAERS. Of 108 dabigatran-dronedarone interaction cases, 51 were associated with bleeding events. The odds ratio (OR) for risk of bleeding in patients using dabigatran and dronedarone concomitantly compared with those using neither of the suspect drugs was 13.80 (95% CI 9.45-20.14). The OR for risk of bleeding in patients using only dabigatran compared with those using neither of the suspect drugs was 16.06 (15.00-17.19). CONCLUSION: The likelihood of reporting bleeding events to FAERS among patients using dabigatran only was similar to that among patients using dabigatran and dronedarone concomitantly.

Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial.

BACKGROUND AND OBJECTIVES: The oral calcitonin gene-related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine. METHODS: In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4-14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function-Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function-Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)-6 scores. RESULTS: Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: -2.54; p = 0.0003; PI: -1.99; and p = 0.0011) and 60 mg groups (PDA: -3.32; p < 0.0001; PI: -2.46; p < 0.0001), but not for the 10 mg group (PDA: -1.19; p = 0.086; PI: -1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. DISCUSSION: Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03777059. Submitted: December 13, 2018; First patient enrolled: December 14, 2018. CLINICALTRIALS: gov/ct2/show/NCT03777059. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that daily atogepant is associated with improvements in health-related quality-of-life measures in patients with 4-14 migraine days per month.

SF-6D utility index as measure of minimally important difference in health status change.

OBJECTIVES: To combine anchor- and distribution-based approaches to identify minimally important differences (MIDs) for the short-form six-dimension utility index (SF-6D) and to identify variables associated with self-reported health status change. DESIGN: Descriptive, exploratory, nonexperimental study. SETTING: United States between April 1, 1999, and October 31, 1999. PATIENTS: 2,317 participants of SADD-Sx (Study of Antihypertensive Drugs and Depressive Symptoms), aged 50 years or older and with hypertension and coronary artery disease. INTERVENTION: Patients were randomized into a verapamil SR- or atenolol-led hypertensive treatment strategy and mailed baseline and 1-year surveys. MAIN OUTCOME MEASURE: SF-6D utility scores for patients completing both surveys. RESULTS: The pooled mean (±SD) MID change on the SF-6D of patients whose health status minimally changed was 0.035 ± 0.095. The anchor-based change scores had a median value of 0.036 (interquartile range -0.03 to 0.10). One-third and one-half of the SD of SF-6D change scores were 0.035 and 0.053, respectively. Whites were less likely to report minimally improved health status compared with nonwhites (odds ratio 0.59 [95% CI 0.40-0.88]). Change in SF-6D scores improved prediction of health status change. CONCLUSION: We recommend using the MID range based on all patients combined (-0.03 to 0.10) to interpret SF-6D scores. These estimates can be used in conjunction with other measures of efficacy to determine meaningful changes. SF-6D demonstrates potential utility in predicting minimally important improvement or worsening among patients receiving different pharmacologic medications.

Cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or standard of care in patients with type 2 diabetes and established cardiovascular disease.

INTRODUCTION: Empagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, is approved in the USA to reduce risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus (T2DM) and established CV disease, based on EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial results. Empagliflozin reduced major adverse CV event (MACE) by 14%, CV death by 38%, and hospitalization for heart failure (HHF) by 35% vs placebo, each on top of standard of care (SoC). SGLT-2 inhibitors canagliflozin and dapagliflozin have also been compared with placebo, all on top of SoC, in CV outcome trials. In the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program, canagliflozin reduced MACE by 14% and HHF by 33%. Dapagliflozin reduced HHF by 27% in the DECLARE-TIMI 58 trial (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events). This analysis estimated the cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or SoC, in US adults with T2DM and established CV disease. RESEARCH DESIGN AND METHODS: Individual patient-level discrete-event simulation was conducted to predict time-to-event for CV and renal outcomes, and specific adverse events over patients' lifetimes. Occurrence of events in EMPA-REG OUTCOME was estimated based on event-free survival curves with time-dependent covariates. An HR for canagliflozin or dapagliflozin versus empagliflozin on each clinical event was estimated from published CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME data using indirect treatment comparison. Public sources provided US costs and utilities. RESULTS: The model predicted longer survival for empagliflozin versus canagliflozin, dapagliflozin, and SoC mainly due to direct reduction in CV death. Empagliflozin dominated canagliflozin, yielding more quality-adjusted life years (QALYs; 0.38) at a lower cost (-US$306). Compared with dapagliflozin and SoC, empagliflozin yielded 0.50 and 0.84 incremental QALYs at US$1517 and US$27 539 incremental costs, yielding incremental cost-effectiveness ratios of US$3054/QALY and US$32 848/QALY, respectively. CONCLUSIONS: Empagliflozin was projected to dominate canagliflozin and be highly cost-effective compared with dapagliflozin and SoC using US healthcare costs.

Quantifying the Risk Continuum for Cardiovascular Death in Adults with Type 2 Diabetes.

OBJECTIVES: In type 2 diabetes (T2D), the most common causes of death are cardiovascular (CV) related, accounting for >50% of deaths in some reports. As novel diabetes therapies reduce CV death risk, identifying patients with T2D at highest CV death risk allows for cost-effective prioritization of these therapies. Accordingly, the primary goal of this study was to quantify the risk continuum for CV death in a real-world T2D population as a means to identify patients with the greatest expected benefit from cardioprotective antidiabetes therapies. METHODS: This retrospective study included patients with T2D receiving services through an integrated health-care system and used data generated through electronic medical records (EMRs). Quantifying the risk continuum entailed developing a prediction model for CV death, creating an integer risk score based on the final prediction model and estimating future CV death risk according to risk score ranking. RESULTS: Among 59,180 patients with T2D followed for an average of 7.5 years, 15,691 deaths occurred, 6,033 (38%) of which were CV related. The EMR-based prediction model included age, established CV disease and risk factors and glycemic indices (c statistic = 0.819). The 10% highest-risk patients according to prediction model elements had an annual CV death risk of ∼5%; the 25% highest-risk patients had an annual risk of ∼2%. CONCLUSIONS: This study incorporated a prediction modelling approach to quantify the risk continuum for CV death in T2D. Prospective application allows us to rank individuals with T2D according to their CV death risk, and may guide prioritization of novel diabetes therapies with cardioprotective properties.

Optimal measurement model is crucial to identify distinct constructs.

This is a Brief Commentary in response to article-"Steinsbekk, S., Jozefiak, T., Ødegård, R., & Wichstrøm, L. (2009). Impaired parent-reported quality of life in treatment-seeking children with obesity is mediated with high levels of psychopathology. Quality of Life Research, 18(9), 1159-1167. doi: 10.1007/s11136-009-9535-6 ." The commentary states that the investigation of the hypothesis if quality of life and psychopathology are two separate constructs may have been hampered by the use of a suboptimal measurement model.