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Bradley E Chipps,1 Robert S Zeiger,2 David A Beuther,3 Robert A Wise,4 William McCann,5 Joan Reibman,6 Maureen George,7 Ileen Gilbert,8 James M Eudicone,8 Karin S Coyne,9 Gale Harding,9 Kevin R Murphy10 1Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 2Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA; 3Department of Medicine, National Jewish Health, Denver, CO, USA; 4Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Allergy Partners, Asheville, NC, USA; 6Department of Medicine, New York University School of Medicine, New York, NY, USA; 7Columbia University School of Nursing, New York, NY, USA; 8BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 9Evidera, Bethesda, MD, USA; 10Boys Town National Research Hospital, Boys Town, NE, USACorrespondence: Bradley E Chipps, Capital Allergy & Respiratory Disease Center, 5609 J Street, Suite C, Sacramento, CA, 95819, USA, Tel +1 916-453-1454, Email bchipps@capitalallergy.com

Joan Reibman,1 Bradley E Chipps,2 Robert S Zeiger,3 David A Beuther,4 Robert A Wise,5 William McCann,6 Ileen Gilbert,7 James M Eudicone,7 Hitesh N Gandhi,7 Gale Harding,8 Katelyn Cutts,8 Karin S Coyne,8 Kevin R Murphy,9 Maureen George10 1New York University School of Medicine, New York, NY, USA; 2Capital Allergy & Respiratory Disease Center, Sacramento, CA, USA; 3Department of Clinical Science Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA; 4National Jewish Health, Denver, CO, USA; 5Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Allergy Partners, Asheville, NC, USA; 7BioPharmaceuticals Medical, AstraZeneca, Wilmington, DE, USA; 8Evidera, Bethesda, MD, USA; 9Boys Town National Research Hospital, Boys Town, NE, USA; 10Office of Research & Scholarship, Columbia University School of Nursing, New York, NY, USACorrespondence: Joan Reibman, New York University School of Medicine, 550 1st Avenue, Room NB7N24, New York, NY, 10016, USA, Tel +1 212-263-6479, Fax +1 212-263-8442, Email joan.reibman@nyumc.orgPurpose: Critical asthma outcomes highlighted in clinical guidelines include asthma-related quality of life, asthma exacerbations, and asthma control. An easy-to-implement measure of asthma control that assesses both symptom impairment and exacerbation risk and reflects the impact of asthma on patients’ lives is lacking. Hence, the objective of this study was to assess the Asthma Impairment and Risk Questionnaire (AIRQ®) construct validity relative to patient self-perception of asthma status and validated disease-specific patient-reported outcome (PRO) measures.Patients and methods: Baseline data were analyzed from patients (aged ≥ 12 years) with asthma participating in a 12-month observational study assessing the ability of AIRQ to predict exacerbations. At entry, patients completed a sociodemographic questionnaire, AIRQ, 3 questions addressing self-perceived asthma status, Saint George’s Respiratory Questionnaire (SGRQ), mini-Asthma Quality of Life Questionnaire (AQLQ), and Adult Asthma Adherence Questionnaire (AAAQ). Descriptive statistics were calculated for demographic and clinical characteristics. AIRQ construct validity was evaluated by assessing correlations between total AIRQ score and patient self-assessments, SGRQ, mini-AQLQ, and AAAQ scores. Comparisons of SGRQ, mini-AQLQ, and AAAQ total and component/domain scores by AIRQ control category were performed using general linear models and Scheffe’s post hoc adjustments for pairwise comparisons.Results: A total of 1112 patients were enrolled: 70% female, 78% White, mean (standard deviation) age 43.9 (19.5) years. There were highly significant correlations between AIRQ score and patient self-perception of overall control (r = 0.69; p < 0.001), total SGRQ (r = 0.74, p < 0.001), and mini-AQLQ (r = − 0.78, p < 0.001) scores. As AIRQ control category worsened, so did total and domain SGRQ, mini-AQLQ, and AAAQ impediment-to-inhaled-corticosteroid-adherence scores (all pairwise comparisons p < 0.001).Conclusion: Findings demonstrate the construct validity of AIRQ relative to patient self-perception of asthma status, disease-specific PRO measures, and treatment adherence barriers. AIRQ can be a useful instrument to raise awareness of the unrecognized impacts of asthma on patients’ lives.Keywords: exacerbation, patient-reported outcomes, construct validity, impact of asthma

Background: In patients with asthma, bronchoconstriction and airway inflammation both contribute to airway narrowing and airflow limitations, which lead to symptoms and exacerbations. Short-acting β₂-agonist (SABA)-only rescue therapy addresses only bronchoconstriction and is associated with increased morbidity and mortality. Current asthma management guidelines recommend concomitant treatment of symptoms and inflammation with a fast-acting bronchodilator and inhaled corticosteroid (ICS) as rescue therapy for patients ≥12 years of age. However, there is an education and outreach gap for the wider adoption of anti-inflammatory rescue therapy in clinical practice. Objective: AstraZeneca has developed an education program for health-care practitioners (HCPs) based on a Knowledge-to-Action Framework, with the aim of increasing HCPs' understanding of key disease-state concepts related to evidence-based management of asthma. Methods: A multichannel, evidence-based education program was presented at medical conferences across the United States between December 2022 and December 2023. Before and after each event, attendees were asked to complete a survey that rated their agreement with six disease-state concepts on a five-point Likert scale. These concepts related to the role of airway inflammation, fluctuations in inflammation, SABA and ICS therapy, and the risk of exacerbations. Postevent responses to the survey were assessed relative to pre-event responses and longitudinally over 12 months by using calculated odds ratios and 95% confidence intervals. Acceptance and/or understanding of a concept was defined as a rating of "agree" or "strongly agree" from at least 80% of respondents. Results: The proportion of respondents who agreed or strongly agreed with each concept was significantly higher postevent versus pre-event (p < 0.001). The 80% acceptance and/or understanding threshold was surpassed for all concepts after the event. Conclusion: The medical education program improved understanding and/or acceptance of key disease-state concepts related to asthma management among participating HCPs. Effective communication of disease management concepts may lead to improved patient health outcomes through more rapid acceptance of guideline-recommended medical therapies.

Background: Asthma in children is a leading cause of missed school days, emergency department visits, and hospitalizations. Approximately 40% of children with asthma experience uncontrolled disease and annual exacerbations. There is a need for a validated composite tool for children, such as the Asthma Impairment and Risk Questionnaire (AIRQ), which was developed to assess current control and predict exacerbations in adolescents and adults with asthma., Objective: To obtain feedback from children with asthma and their parents/caregivers to inform development of a version of the AIRQ for pediatric use (Peds-AIRQ)., Methods: Children with asthma aged 5 to 11 years and their parents/caregivers participated in cognitive interviews to elicit language describing asthma symptoms and exacerbations and to assess understanding and relevance of draft Peds-AIRQ questions. Physicians and parents/caregivers provided clinical information and performed assessments relative to the children's asthma morbidity., Results: There were 60 dyads that participated: children's mean (SD) age = 7.9 (1.9) years; 68% male, 45% non-White, 32% Hispanic, and 40% with public health insurance. Overall, 53% had well-controlled, 30% partly controlled, and 17% uncontrolled asthma, based on the Global Initiative for Asthma symptom control questions. Oral or injected corticosteroids were used for asthma by 53% of the children in the previous year. Participants found draft Peds-AIRQ items understandable and relevant. Seven impairment and 3 risk questions were retained for validation, along with 5 additional items containing wording or control threshold variations., Conclusion: This study supports the need for developing a composite (impairment and risk) control tool to assess children aged 5 to 11 years with asthma and identified suitable questions for the validation of a Peds-AIRQ., Competing Interests: Disclosures Dr Lanz is a consultant for Amgen, AstraZeneca, Cogent, Genentech, Grifols, Novartis, and Sanofi/Regeneron; is a speaker for Amgen/AstraZeneca and Sanofi/Regeneron; and receives research grants from Regeneron, Sanofi, Genentech/Roche, and AstraZeneca. Dr Chipps has served as an advisor, consultant, and speaker for AstraZeneca, Boehringer Ingelheim, Circassia, Genentech, Novartis, Regeneron, and Sanofi. Dr Zeiger has received grants from Aerocrine, Genentech, MedImmune/AstraZeneca, Merck, GlaxoSmithKline, ALK Pharma, Teva, Sanofi, and the National Heart, Lung, and Blood Institute, has received consultant fees from AstraZeneca, Bayer, Genentech/Novartis, Merck, and Regeneron, and holds warrant shares in DBV Technologies. Dr Bacharier is a consultant for AstraZeneca, GlaxoSmithKline, Regeneron Pharmaceuticals Inc, Sanofi, Recludix, and Avillion; is a speaker for Sanofi and Regeneron; is a member of the data and safety monitoring board for AstraZeneca, Cystic Fibrosis Foundation/Vertex, Aravax, and DBV Technologies; and receives research support from the National Institutes of Health, AstraZeneca, and Sanofi. Dr Guilbert is a consultant for Amgen, AstraZeneca, Genentech, OM Pharma, Regeneron, and Sanofi; receives grants from Amgen, AstraZeneca, GlaxoSmithKline, OM Pharma, Regeneron, and Sanofi; and receives personal fees from Advent.com, AiCME, AstraZeneca, Genentech, OM Pharma, PlatformQ health, and Polarean. Dr Murphy has served as a consultant and is a speaker for AstraZeneca, Boehringer Ingelheim, Genentech, Greer, Merck, Mylan, Novartis, Regeneron, Sanofi, OptiNose, and Teva. Ms Winders is a consultant/speaker for ALK, AstraZeneca, Chiesi, Genentech, GlaxoSmithKline, Roche, Sanofi, and Regeneron. Dr Mohammad has participated on an advisory board for AstraZeneca. Ms LeNoir has participated on an advisory board for AstraZeneca and is a board member at Digital Health Equitable Alliance and African American Wellness Project. Dr Gilbert and Mr Eudicone are employees of AstraZeneca, the sponsor of this study, and may hold stock or stock options. Dr Coyne and Ms Harding are employees of Evidera, which was contracted by AstraZeneca for study design support, to collect and analyze data for this study, and to provide medical writing support. Dr George has served as a consultant to AstraZeneca, Insmed, and Teva and has served as a speaker for AstraZeneca and Regeneron., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The optimal approach towards managing serum potassium (sK + ) and hemodialysate potassium concentrations is uncertain. To study this, adults receiving hemodialysis for three months or more with hyperkalemia (pre-dialysis sK + 5.1-6.5 mmol/l) had cardiac monitors implanted and were randomized to either eight weeks of 2.0 mmol/l potassium/1.25 mmol/l calcium dialysate without sodium zirconium cyclosilicate (SZC) (2.0 potassium/noSZC) or 3.0 mmol/l potassium/1.25 mmol/l calcium dialysate combined with SZC (3.0 potassium/SZC) on non-dialysis days to maintain pre-dialysis sK + 4.0-5.5 mmol/l, followed by treatment crossover for another eight weeks. The primary outcome was the rate of adjudicated atrial fibrillation (AF) episodes of at least 2 minutes duration. Secondary outcomes included clinically significant arrhythmias (bradycardia, ventricular tachycardia, and/or asystole) and the proportion of sK + measurements within an optimal window of 4.0-5.5 mmol/l. Among 88 participants (mean age: 57.1 years; 51% male; mean pre-dialysis sK + : 5.5 mmol/l) with 25.5 person-years of follow-up, 296 AF episodes were detected in nine patients. The unadjusted AF rate was lower with 3.0 potassium/SZC versus 2.0 potassium/noSZC; 9.7 vs. 13.4/person-year (modeled rate ratio 0.52; 95% confidence interval 0.41-0.65). Clinically significant arrhythmias were reduced with 3.0 potassium/SZC vs. 2.0 potassium/noSZC (6.8 vs. 10.2/person-year modeled rate ratio 0.47; 0.38; 0.58). Fewer sK + measurements outside the optimal window occurred with 3.0 potassium/SZC (modeled odds ratio: 0.27; 0.12-0.35). Hypokalemia was less frequent (33 vs. 58 patients) with 3.0 potassium/SZC compared with 2.0 potassium/noSZC. Thus, in patients with hyperkalemia on maintenance hemodialysis, a combination of hemodialysate potassium 3.0 mmol/l and SZC on non-hemodialysis days reduced the rates of AF, other clinically significant arrhythmias, and post-dialysis hypokalemia compared with hemodialysate potassium 2.0/noSZC., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA., Objectives: This study sought to evaluate the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia., Methods: REALIZE-K (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA-induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/day); those with hyperkalemia started SZC. Participants with normokalemia (potassium: 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/day were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/day without rescue therapy for hyperkalemia [months 1-6]). The 5 secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening heart failure (HF) events (hospitalizations and urgent visits)., Results: Overall, 203 participants were randomized (SZC: 102; placebo: 101). Higher percentage of SZC- vs placebo-treated participants had optimal response (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; P < 0.001). SZC (vs placebo) improved the first 4 secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR: 4.58; 95% CI: 2.78-7.55; P < 0.001); receiving spironolactone ≥25 mg/day (81% vs 50%; OR: 4.33; 95% CI: 2.50-7.52; P < 0.001); time to hyperkalemia (HR: 0.51; 95% CI: 0.37-0.71; P < 0.001); and time to decrease/discontinuation of spironolactone due to hyperkalemia (HR: 0.37; 95% CI: 0.17-0.73; P = 0.006). There was no between-group difference in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at 6 months (-1.01 points; 95% CI: -6.64 to 4.63; P = 0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of cardiovascular (CV) death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal P = 0.034)., Conclusions: In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalemia and down-titration/discontinuation of spironolactone. Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone; NCT04676646)., Competing Interests: Funding Support and Author Disclosures The REALIZE-K trial was funded by AstraZeneca. Dr Kosiborod will become an AstraZeneca BioPharmaceuticals Research and Development Employee as Senior Vice President for Late Stage Cardiovascular, Renal and Metabolic Disease, effective January 6, 2025; this role entails development oversight for several compounds, including SZC. During conduction of the trial, Dr Kosiborod acted as the Primary Investigator from an independent academic research organization; he was not an employee of AstraZeneca during the design or conduction of the REALIZE-K trial or at the time of manuscript submission; has received research grants (payment to institution) from AstraZeneca, Boehringer Ingelheim, and Pfizer; has received consultant/advisory board fees (payment to institution) from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Roche, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support (payment to institution) from AstraZeneca and Vifor Pharma; has received honoraria (payment to institution) from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and owns stock options in Artera Health and Saghmos Therapeutics. Dr Cherney has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GlaxoSmithKline, and Novo Nordisk; and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Novo Nordisk, and Bayer. Dr Desai has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, DevPro Biopharma, Novartis, Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, scPharmaceuticals, Verily, and Zydus. Dr Testani has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and has received grants and/or research support and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management Inc, Sanofi, and Sun Pharmaceuticals; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Chinnakondepalli has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Dolling is an employee of Fortrea, which received a consultancy fee for the conduct of the current study from AstraZeneca. Dr Patel has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Mr Dahl, Mr Eudicone, Ms Friberg, and Dr Ouwens are employees of and hold or may hold stock in AstraZeneca. Dr Antunes has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Connelly is supported by the Keenan Chair in research leadership; and has received research funding in the form of grants and/or consulting for AstraZeneca. Dr Kuthi has received lecture fees from Boehringer, Novartis, and Richter (outside of the submitted work). Dr Lala has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Lorenzo has received honoraria for lectures from AstraZeneca, Bayer, Novartis, and Viatris (outside of the submitted work). Dr Marcos has received honoraria for lectures or advisory boards from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Rovi, and Vifor CSL (outside of the submitted work). Dr Nuñez has received honoraria for lectures or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, and Vifor CSL (outside of the submitted work). Dr Merkely has received lecture fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL-Behring, Daiichi-Sankyo, Medtronik, and Novartis. Dr Squire has received speaker fees from PharmaCosmos; and his research department has received funding for research from Novartis, AstraZeneca, Boehringer Ingelheim, PharmaCosmos, the British Heart Foundation, and the National Institute for Health Research. Dr Wranicz has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Petrie has received research grants or contracts from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, SQ Innovations, and 3R LifeSciences; has received consulting fees or honoraria from Abbvie, Abott, Akero, Applied Therapeutics, Amgen, AnaCardio, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corteria, Corvia, Eli Lilly, FIRE 1, Foundry, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Regeneron, Reprieve, Siemens, Takeda, Teikoku, Vifor, and 3R Lifesciences; and has participated on Data and Safety Monitoring Boards from AstraZeneca, Moderna, and Teikoku. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns., Objectives: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk)., Methods: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6])., Results: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m 2 , 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily., Conclusions: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646)., Competing Interests: Funding Support and Author Disclosures The REALIZE-K trial was funded by AstraZeneca. Drs Kosiborod, Cherney, Connelly, Desai, Guimarães, Kuthi, Lala, Madrini, Merkely, Villota, Squire, Testani, Vaclavik, Verma, Wranicz, and Petrie have received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Mr Dahl, Mr Eudicone, and Ms Friberg are employees of, and hold or may hold stock in, AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Complex models combining impairment-based control assessments with clinical characteristics and biomarkers have been developed to predict asthma exacerbations. The composite Asthma Impairment and Risk Questionnaire (AIRQ) with adjustments for demographics (age, sex, race, and body mass index) predicts 12-month exacerbation occurrence similarly to these more complex models., Objective: To examine whether AIRQ exacerbation prediction is enhanced when models are adjusted for a wider range of clinical characteristics and biomarkers., Methods: Patients aged 12 years and older completed monthly online surveys regarding exacerbation-related oral corticosteroid use, emergency department or urgent care visits, and hospitalizations. Univariate logistic regressions to predict exacerbations were performed with sociodemographics, comorbidities, exacerbation history, lung function, blood eosinophils, IgE, and FeNO. Significant (P ≤ .05) variables were included in multivariable logistic regressions with and without AIRQ control categories to predict 12-month exacerbations (log odds ratio [95% Wald confidence interval]). Model performances were compared., Results: Over 12 months, 1,070 patients (70% female; mean [SD] age, 43.9 [19.4] years; 22% non-White; body mass index [SD], 30.6 [8.7]) completed one or more survey (mean [SD], 10.5 [2.8] surveys). In the multivariable analysis, AIRQ control category adjusted for significant clinical characteristics and biomarkers was predictive of one or more exacerbations: odds ratio (95% CI) not well-controlled versus well-controlled: 1.93 (1.41-2.62), very poorly controlled versus well-controlled: 3.81 (2.65-5.47). Receiver operating characteristic area under the curve (AUC) for this more complex model of exacerbation prediction (AUC = 0.72) did not differ from AIRQ (AUC = 0.70). Models with AIRQ performed better than those without AIRQ (AUC = 0.67; P < .05)., Conclusion: Costly and time-consuming complex modeling with clinical characteristics and biomarkers does not enhance the strong exacerbation prediction ability of AIRQ., (Copyright © 2024. Published by Elsevier Inc.)

Background: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, yes/no, equally weighted control tool. Lower scores indicate better control. Moreover, 7 impairment items reflect previous 2-week symptoms, and 3 risk items assess previous 12-month exacerbations. The Follow-up AIRQ for use between annual assessments has a 3-month recall period for exacerbation items., Objective: To evaluate the responsiveness of the AIRQ over time and identify a minimal important difference (MID)., Methods: The AIRQ longitudinal study data were analyzed from patients with asthma aged 12 years and older. Anchor-based methods assessed differences in AIRQ scores relative to Patient Global Impression of Change, the accepted MIDs for St. George's Respiratory Questionnaire and Asthma Control Test, and exacerbation occurrence over 12 months. Baseline and 12-month data reflected 12-month recall AIRQ scores; Follow-up AIRQ scores were used for 3-, 6-, and 9-month analyses., Results: A total of 1070 patients were included. The Patient Global Impression of Change rating of "much improved" was associated with AIRQ mean score changes from baseline to months 3, 6, 9, and 12 of -2.0, -1.9, -1.9, and -1.8, respectively. The mean AIRQ score change among patients who met the St. George's Respiratory Questionnaire MID (≥4-point decrease) was -1.8 at 6 and 12 months. The AIRQ mean scores decreased from baseline by -2.2 to -2.5 points at months 3, 6, 9, and 12 for patients who met the Asthma Control Test MID (≥ 3-point increase). A 2-point higher baseline AIRQ score was associated with a 1.7 odds ratio of 12-month exacerbation occurrence (95% CI, 1.53-1.89)., Conclusion: A change score of 2 is recommended as the AIRQ MID., Competing Interests: Disclosures Dr McCann has served as a consultant and speaker for AstraZeneca, a speaker for Regeneron, and a consultant for Aimmune and Genentech. Dr Murphy has served as a consultant and is a speaker for AstraZeneca, Boehringer Ingelheim, Genentech, Greer, Merck, Mylan, Novartis, Regeneron, Sanofi, Optinose, and Teva. Dr Zeiger has received grants from Aerocrine, Genentech, MedImmune/AstraZeneca, Merck, GlaxoSmithKline, Teva, Quest, Sanofi, and the National Heart, Lung, and Blood Institute; has completed consultant activity for AstraZeneca, Regeneron, Merck, Genentech/Novartis, and Bayer; and holds warrant shares in DBV Technologies. Dr Beuther has participated in advisory boards for AstraZeneca. Dr Wise received consultant fees and honoraria from AstraZeneca, GlaxoSmithKline, Novartis, Boehringer Ingelheim, ContraFect, Pulmonx, Roche, Regeneron, AbbVie, Spiration, Sunovion, Merck, Circassia, Pneuma, Verona, Bonti, Denali, Aradigm, Mylan, Theravance, Propeller Health, Kiniksa, and Syneos. Dr Reibman has served as an advisory committee member for AstraZeneca, received grant/research support from Novartis, served on an advisory board for Novartis and Genentech, and participated in clinical trials funded by AstraZeneca, Novartis, and Teva. Dr George has served as a consultant and speaker to AstraZeneca, Regeneron, and Sanofi. Dr Gilbert and Mr Eudicone are employees of AstraZeneca. Dr Gandhi was an employee of AstraZeneca at the time this work was completed and is a current employee of Alexion, AstraZeneca Rare Disease. Ms Cutts and Dr Coyne are employees of Evidera, which was contracted by AstraZeneca for study design and to collect and analyze data for this study. Dr Chipps has served as an advisor, consultant, and speaker for AstraZeneca, Boehringer Ingelheim, Circassia, Genentech, Novartis, Regeneron, and Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: National and international asthma guidelines and reports do not include control tools that combine impairment assessment with exacerbation history in one instrument., Objective: To analyze the performance of the composite Asthma Impairment and Risk Questionnaire (AIRQ) in assessing both domains of control and predicting exacerbation risk compared with the Global Initiative for Asthma (GINA) 4-question symptom control tool (GINA SCT), Asthma Control Test (ACT), and physician expert opinion (EO) informed by GINA SCT responses and appraisal of GINA-identified risk factors for poor asthma outcomes., Methods: Multivariable logistic regressions evaluated AIRQ and GINA SCT as predictors of ACT. McNemar's test compared the proportion of patients categorized at baseline as completely or well-controlled by each assessment but with current impairment or previous-year and subsequent-year exacerbations., Results: The analysis included 1064 patients aged 12 years or older; mean (SD) age 43.8 years (19.3); 70% female; 79% White; and 6% Hispanic or Latino. AIRQ and GINA SCT were highly predictive of ACT well-controlled vs not well-controlled and very poorly controlled (receiver operator characteristic area under curve AIRQ = 0.90, GINA SCT = 0.86, P = .03 AIRQ vs GINA SCT) and ACT very poorly controlled vs well-controlled and not well-controlled asthma (receiver operator characteristic area under curve AIRQ = 0.91, GINA SCT = 0.87, P = .01 AIRQ vs GINA SCT). AIRQ rated fewer patients as having completely or well-controlled asthma who had current impairment (P < .01) or with previous-year and subsequent-year exacerbations (P < .001) than did GINA SCT, ACT, and EO., Conclusion: AIRQ performs better in assessing both domains of current control and predicting exacerbation risk than do control tools and EO informed by GINA SCT and risk factors for poor asthma outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patient perception of medication onset of effect is important for adherence. Although the Onset of Effect Questionnaire (OEQ) has been validated in patients with asthma, it has not been evaluated in patients with chronic obstructive pulmonary disease (COPD). This study evaluated the COPD-OEQ in patients with COPD., Methods: Two analyses (qualitative and quantitative) were conducted to assess the content validity and psychometric properties of the COPD-OEQ in participants with COPD. In the qualitative analysis, interviews assessed content validity by concept elicitation (CE) and cognitive interviewing (CI). CE included questions to understand patient experience related to onset of medication effect. CI included completion of the COPD-OEQ and assessment of the COPD-OEQ items, response options, and instructions. During the 2-week quantitative analysis, 2 versions of the COPD-OEQ (Weekly and Daily) were administered to assess test-retest reliability, construct validity, and known-groups validity., Results: The qualitative analysis demonstrated that 3 of the 5 COPD-OEQ items were relevant and understood as intended. Qualitative findings demonstrated inconsistent evidence that the COPD-OEQ Weekly and Daily were reliable and valid measures in participants with COPD. Test-retest reliability was observed for the COPD-OEQ Weekly and Daily; however, construct validitywas weak and demonstrated inconsistent correlations among COPD-OEQ items. Overall, known-groups validity was not demonstrated., Conclusion: The weak evidence from the quantitative analysis of the COPD-OEQ Weekly and Daily tools does not support use of the OEQ in general COPD. The study supports the content validity for the assessment of perceived onset of effect in patients with COPD., (JCOPDF © 2024.)

Background: Asthma control is often overestimated in routine practice, and despite advances in the understanding of immunopathology and the availability of new precision therapies, the burden of disease remains unacceptably high., Objective: To compare the performance of the Asthma Impairment and Risk Questionnaire (AIRQ) with patient and physician assessments and the Asthma Control Test (ACT) in identifying asthma control., Methods: Baseline data from a longitudinal study of the AIRQ were analyzed. Patients with asthma in the United States aged 12 years and older followed in 24 specialty practices and 1 specialty-affiliated primary care clinic were enrolled between May and November 2019. At entry, participants completed AIRQ and ACT, and participants and physicians completed 5-point Likert scale assessments of control., Results: A total of 1112 participants were enrolled (mean [SD] age = 43.9 [19.3] years, 70% of the female sex, 78% White). Overall, 62% of participants rated themselves as well- or completely controlled, and 54% were rated comparably by physicians. The ACT classified 49% of participants as well-controlled, with 35% similarly categorized by AIRQ. Previous-year exacerbations were experienced by 32% of participants who self-rated as well- or completely controlled, 30% who were rated as well- or completely controlled by physicians, and 29% assessed as well-controlled by ACT, but only 15% of those classified as well-controlled by AIRQ., Conclusion: The burden of asthma is substantial in patients cared for by asthma specialists, and asthma control is overestimated by patients, physicians, and the symptom-based ACT. The AIRQ assesses risk in addition to symptom control and may serve to improve asthma control determination by assessing previous exacerbations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Individuals with chronic kidney disease (CKD) hospitalized with hyperkalemia are at risk of hyperkalemia recurrence and re-hospitalization. We present the rationale and design of CONTINUITY, a study to examine the efficacy of continuing sodium zirconium cyclosilicate (SZC)-an oral, highly selective potassium (K + ) binder-compared with standard of care (SoC) on maintaining normokalemia and reducing re-hospitalization and resource utilization among participants with CKD hospitalized with hyperkalemia., Methods: This Phase 4, randomized, open-label, multicenter study will enroll adults with Stage 3b-5 CKD and/or estimated glomerular filtration rate <45 mL/min/1.73 m 2 , within 3 months of eligibility screening, hospitalized with a serum potassium (sK + ) level of >5.0-≤6.5 mmol/L, without ongoing K + binder treatment. The study will include an in-hospital phase, where participants receive SZC for 2-21 days, and an outpatient (post-discharge) phase. At discharge, participants with sK + 3.5-5.0 mmol/L will be randomized (1:1) to SZC or SoC and monitored for 180 days. The primary endpoint is the occurrence of normokalemia at 180 days. Secondary outcomes include incidence and number of hospital admissions or emergency department visits both with hyperkalemia as a contributing factor, and renin-angiotensin-aldosterone system inhibitor down-titration. The safety and tolerability of SZC will be evaluated.Ethics approval has been received from all relevant ethics committees. Enrollment started March 2022 and the estimated study end date is December 2023., Conclusions: This study will assess the potential of SZC versus SoC in managing people with CKD and hyperkalemia post-discharge., Trial Registration: ClinicalTrials.gov identifier: NCT05347693; EudraCT: 2021-003527-14, registered on 19 October 2021., Competing Interests: This information presented in this manuscript has not been published previously in whole or part, except in abstract format (Nephrol Dialysis Transplant 2022;37:gfac066.053). J.O.B. holds grant funding from the National Institute of Health Research, the British Heart Foundation, Kidney Research UK and Yakult Honsha. He has received honoraria from AstraZeneca, Napp Pharmaceutical Group Ltd, Vifor Pharma, Pfizer/Bristol-Myers Squibb and Astellas. A.M.A., J.M.E., E.L. and C.M. are employees of, and hold or may hold stock in, AstraZeneca. A.A. reports serving as principal investigator or co-investigator of clinical trials sponsored by the National Institutes of Health/National Institute of Allergy and Infectious Diseases, NeuroRx Pharma, Pulmotect, Inc., Blade Therapeutics, Novartis, Takeda, Humanigen, Eli Lilly, PTC Therapeutics, Octapharma, Fulcrum Therapeutics and Alexion, unrelated to the present study; speaker and/or consultant for Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Portola, Sunovion, Mylan, Salix, Alexion, AstraZeneca, Novartis, Nabriva Therapeutics, Paratek Pharmaceuticals, Inc., Bayer, Tetraphase Pharmaceuticals, Inc., Achogen La Jolla, Ferring, Seres, Spero, Eli Lilly, Millennium, PeraHealth, HeartRite, AseptiScope and Sprightly, unrelated to the present study. C.L. reports consulting fees from AstraZeneca, Roche diagnostics and Bayer; and speaker honoraria from Novartis, Astra, Bayer, Medtronic, Impulse Dynamics and Vifor Pharma. M.M.S., holder of the Jindal Research Chair in the Prevention of Kidney Disease, has received honoraria from AstraZeneca., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: The Asthma Impairment and Risk Questionnaire (AIRQ) is a 10-item, equally weighted, yes/no control tool validated in patients with asthma aged 12 years and older., Objective: To evaluate AIRQ's ability to predict patient-reported exacerbations over 12 months., Methods: Patients completed a baseline AIRQ during an in-person enrollment visit and reported exacerbations (ie, asthma-related courses of oral corticosteroids, emergency department/urgent care visits, and hospitalizations) via monthly online surveys. Logistic regressions were performed using AIRQ control level (well-controlled [WC], not well-controlled [NWC], very poorly controlled [VPC]), age, sex, race, and body mass index as covariates and 1 or more and 2 or more exacerbations as the dependent variables (adjusted odds ratios [OR] and 95% Wald CIs). Kaplan-Meier analyses of time to first exacerbation by AIRQ control level were performed., Results: A total of 1,112 patients were enrolled; 1,070 completed 1 or more surveys over 12 months (mean ± SD 10.5 ± 2.8 months); 70.5% female; age 43.9 ± 19.3 years; 20.4% non-White; body mass index 30.6 ± 8.7 kg/m 2 ; AIRQ: WC 35.2%, NWC 38.1%, VPC 26.6%. A total of 45.7% of patients reported 1 or more exacerbations and 26.7% 2 or more exacerbations (WC 28.4% ≥ 1, 11.1% ≥ 2; NWC 46.3% ≥ 1, 27.9% ≥ 2; VPC 67.7% ≥ 1, 45.6% ≥ 2). The ORs for 1 or more exacerbations NWC versus WC were 2.1 (CI 1.6-2.9), and VPC versus WC were 4.6 (CI 3.3-6.5). The ORs for 2 or more exacerbations NWC versus WC were 3.1 (CI 2.1-4.6), and VPC versus WC were 6.1 (CI 4.0-9.1). Kaplan-Meier curves demonstrated clear differentiation of time to first exacerbation by AIRQ control level (P < .001)., Conclusions: The AIRQ control level predicts exacerbation risk over 12 months and probability of time to first exacerbation., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Recurrent assessment of asthma control is essential to evaluating disease stability and intervention impacts. An assessment that can be administered between annual clinic visits is needed. The Asthma Impairment and Risk Questionnaire (AIRQ) is a cross-sectionally validated, 10-item, yes or no, composite control tool evaluating previous 2-week symptoms and previous 12-month exacerbations., Objective: To evaluate the construct validity of the AIRQ using a 3-month recall period for exacerbation-based risk questions and retaining the 2-week recall for symptom-based impairment items., Methods: At baseline, patients completed the AIRQ with 12-month recall exacerbation items, Asthma Control Test (ACT), St. George's Respiratory Questionnaire (SGRQ), and global self-assessments of asthma risk, control, and symptom severity. Patient-reported exacerbations were captured monthly. The AIRQ with 3-month recall exacerbation items, ACT, and global self-assessments was administered at months 3, 6, and 9, and SGRQ at month 6., Results: A total of 1112 patients aged 12 years or older were enrolled (mean [SD] age, 43.9 [19.5] years). The AIRQ and each administration of the AIRQ with 3-month recall exacerbation items classified asthma control similarly to an ACT plus exacerbation validation standard. For both AIRQ versions, SGRQ scores were higher with worsening asthma control (P < .001). At months 3, 6, and 9, worse AIRQ control levels were associated with higher proportions of patients with 1 or more and 2 or more exacerbations in the previous 3 months and patient global self-assessments indicating greater asthma morbidity (all P < .001)., Conclusion: The AIRQ using exacerbation risk items with a 3-month recall period exhibits construct validity for classifying current asthma control and can be administered between annual AIRQ assessments., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Telemonitoring is a promising self-management strategy to improve health care outcomes. This study evaluated real-world adoption of the chronic obstructive pulmonary disease (COPD) Co-Pilot daily symptom monitoring tool by patients and primary care providers (PCPs)., Methods: An open-label, 6-month, single-arm, multicenter, noninterventional feasibility study enrolled 97 patients aged ≥ 40 years with symptomatic or poorly controlled COPD and ≥ 10 pack-year smoking history. Patients received smartphones and training to use the COPD Co-Pilot application. During the study, patients tracked symptoms daily; an increase in symptom score of ≥ 1.0 point from baseline (symptom alert) prompted patients to contact their PCP via toll-free number. The primary endpoint was time to clinical recommendation (TTCR) from a symptom alert; adherence to completing daily symptom reports through the COPD Co-Pilot application and patient satisfaction were also measured., Results: Overall, 87 of 96 patients (90.6%) received 2142 symptom alerts; 42 alerts (equivalent to 2% of all symptom alerts) resulted in 23 patients contacting their PCP. Median TTCR was 7.1 h (interquartile range [IQR]: 4.0-29.9). Among 15 patients using the toll-free number, median TTCR was 2.1 h (IQR 0.0-7.2) versus 19.6 h (IQR 4.5-45.2) for eight patients using other contact methods. Average COPD Co-Pilot adherence overall was 75.2% (95% CI 74.6-75.9). Patients responded favorably regarding the application's ease of use, functionality, and information provided., Conclusions: The COPD Co-Pilot tool was associated with relatively high levels of adherence, suggesting patients' willingness to monitor symptoms daily. Although a limited number of patients initiated PCP contact, patients who used the study-provided toll-free number had substantially shorter median TTCR, suggesting that this tool could help empower patients to better manage their COPD., (© 2021. The Author(s).)

Background: A variety of dual-combination maintenance inhalers are used to treat asthma and chronic obstructive pulmonary disease (COPD). Understanding patient preferences for treatment attributes may help select an optimal treatment from the patient perspective., Methods: Patient preferences for maintenance inhaler device and medication attributes were elicited through a discrete choice experiment and used in benefit-risk assessments to calculate predicted choice probabilities (PrCPs) for 14 dual-combination maintenance inhalers in four treatment classes: lower- and higher-dose inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) inhalers for asthma, and ICS/LABA and long-acting muscarinic antagonist (LAMA)/LABA inhalers for COPD., Results: For all treatment classes, reduced exacerbations and faster onset of action were the most important attributes. For all classes, patients were willing to tolerate an extra yearly exacerbation to decrease the medication's onset of action from 30 to 5 min. For patients with asthma using lower-dose ICS/LABA (n = 497), budesonide/formoterol fumarate dihydrate (80 μg/4.5 μg) pressurized metered-dose inhaler (pMDI) had the highest PrCP (28.4%), and for those using a higher-dose ICS/LABA (n = 285), PrCPs were highest for mometasone furoate/formoterol fumarate dihydrate (200 μg/5 μg) pMDI (27.0%) and budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI (26.9%). For patients with COPD using an ICS/LABA (n = 574), budesonide/formoterol fumarate dihydrate (160 μg/4.5 μg) pMDI had the highest PrCP (56.6%), and for those using a LAMA/LABA inhaler (n = 217), tiotropium/olodaterol (2.5 μg/2.5 μg) soft mist inhaler had the highest PrCP (42.3%)., Conclusions: Patient preference data for maintenance inhaler attributes can be used to identify a preference order of inhalers in different treatment classes., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Asthma exacerbation risk increases with worsening asthma control. Prevailing numerical control tools evaluate only current symptom impairment despite the importance of also assessing risk based on exacerbation history. An easy-to-use questionnaire addressing impairment and risk domains of control is needed., Objective: To validate a composite asthma control tool that includes impairment and risk assessments (Asthma Impairment and Risk Questionnaire [AIRQ])., Methods: Four-hundred forty-two patients aged ≥12 years with physician-diagnosed asthma who were followed in specialty practices completed 15 impairment and risk questions with dichotomized yes/no responses. Patients spanned all Global Initiative for Asthma severities and were classified as well-controlled, not well-controlled, or very poorly controlled according to a standard of Asthma Control Test (ACT) score plus prior-year exacerbations. Logistic regression analyses identified questions with the greatest predictive validity to discriminate among patients and determine cut points for these 3 classifications., Results: The final AIRQ comprises 10 equally weighted yes/no impairment and risk questions. The final 10-item models yielded receiver operating characteristic curves of 0.94 to identify well-controlled versus not well-/very poorly controlled and 0.93 to identify well-/not well-controlled versus very poorly controlled asthma, as reflected by the ACT plus prior-year exacerbations standard. Cut points of 0-1, 2-4, and 5-10 best represented well-, not well-, and very poorly controlled asthma., Conclusions: AIRQ is a rigorously validated composite measure designed to identify adults and adolescents with varying degrees of asthma control. Ongoing investigations will determine test-retest reliability, responsiveness to change, and predictive ability for future exacerbations., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Cost is frequently cited as a barrier to optimal medication use, but the extent to which copayment assistance interventions are used when available, and their impact on evidence-based medication persistence and major adverse cardiovascular events is unknown., Methods and Results: The ARTEMIS trial (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) randomized 301 hospitals to usual care versus the ability to provide patients with vouchers that offset copayment costs when filling P2Y 12 inhibitors in the 1 year post-myocardial infarction. In the intervention group, we used multivariable logistic regression to identify patient and medication cost characteristics associated with voucher use. We then used this model to stratify both intervention and usual care patients by likelihood of voucher use, and examined the impact of the voucher intervention on 1-year P2Y 12 inhibitor persistence (no gap in pharmacy supply >30 days) and major adverse cardiovascular events (all-cause death, myocardial infarction, or stroke). Among 10 102 enrolled patients, 6135 patients were treated at hospitals randomized to the copayment intervention. Of these, 1742 (28.4%) never used the voucher, although 1729 (99.2%) voucher never-users filled at least one P2Y 12 inhibitor prescription in the 1 year post-myocardial infarction. Characteristics most associated with voucher use included: discharge on ticagrelor, planned 1-year course of P2Y 12 inhibitor treatment, white race, commercial insurance, and higher out-of-pocket medication costs (c-statistic 0.74). Applying this propensity model to stratify all enrolled patients by likelihood of voucher use, the intervention improved medication persistence the most in patients with high likelihood of voucher use (adjusted interaction P =0.03, odds ratio, 1.86 [95% CI, 1.48-2.33]). The intervention did not significantly reduce major adverse cardiovascular events in any voucher use likelihood group, although the odds ratio was lowest (0.86 [95% CI, 0.56-1.16]) among patients with high likelihood of voucher use (adjusted interaction P =0.04)., Conclusions: Among patients discharged after myocardial infarction, those with higher copayments and greater out-of-pocket medication costs were more likely to use a copayment assistance voucher, but some classes of patients were less likely to use a copayment assistance voucher. Patients at low likelihood of voucher use benefitted least from copayment assistance, and other interventions may be needed to improve medication-taking behaviors and clinical outcomes in these patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02406677.

Background Hospitals commonly provide a short-term supply of free P2Y 12 inhibitors at discharge after myocardial infarction, but it is unclear if these programs improve medication persistence and outcomes. The ARTEMIS (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) trial randomized hospitals to usual care versus waived P2Y 12 inhibitor copayment costs for 1-year post-myocardial infarction. Whether the impact of this intervention differed between hospitals with and without pre-existing medication assistance programs is unknown. Methods and Results In this post hoc analysis of the ARTEMIS trial, we examined the associations of pre-study free medication programs and the randomized copayment voucher intervention with P2Y 12 inhibitor persistence (measured by pharmacy fills and patient report) and major adverse cardiovascular events using logistic regression models including a propensity score. Among 262 hospitals, 129 (49%) offered pre-study free medication assistance. One-year P2Y 12 inhibitor persistence and major adverse cardiovascular events risks were similar between patients treated at hospitals with and without free medication programs (adjusted odds ratio 0.93, 95% CI, 0.82-1.05 and hazard ratio 0.92, 95% CI, 0.80-1.07, respectively). The randomized copayment voucher intervention improved persistence, assessed by pharmacy fills, in both hospitals with (53.6% versus 44.0%, adjusted odds ratio 1.45, 95% CI, 1.20-1.75) and without (59.0% versus 48.3%, adjusted odds ratio 1.46, 95% CI, 1.25-1.70) free medication programs ( P interaction =0.71). Differences in patient-reported persistence were not significant after adjustment. Conclusions While hospitals commonly report the ability to provide free short-term P2Y 12 inhibitors, we did not find association of this with medication persistence or major adverse cardiovascular events among patients with insurance coverage for prescription medication enrolled in the ARTEMIS trial. An intervention that provided copayment assistance vouchers for 1 year was successful in improving medication persistence in hospitals with and without pre-existing short-term medication programs. Registration URL: https://www.clini​caltr​ials.gov/. Unique identifier: NCT02406677.

Objectives: Guidance to industry from the FDA requires studies to evaluate the cardiovascular safety of novel type 2 diabetes (T2D) medications. Although the objectives of such cardiovascular outcomes trials (CVOTs) are similar, differences in features such as enrollment criteria present a challenge when trying to assess the applicability of these studies to real-world T2D populations. This study evaluated the proportions of US adults with T2D who met the eligibility criteria for each of the 4 sodium-glucose cotransporter-2 (SGLT2) inhibitor CVOTs., Study Design: A cross-sectional retrospective study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) and published patient eligibility criteria for completed or ongoing SGLT2 inhibitor CVOTs., Methods: Data on T2D diagnosis and other relevant clinical and demographic characteristics were extracted from the NHANES (2009-2010 and 2011-2012). Weighted analysis of these data was used to estimate the percentage of US adults with T2D who met the eligibility criteria for the CANVAS program (CANagliflozin cardioVascular Assessment Study) (canagliflozin; NCT01032629, NCT01989754), and the DECLARE-TIMI 58 (dapagliflozin; NCT01730534), EMPA-REG OUTCOME (empagliflozin; NCT01131676), and VERTIS-CV (ertugliflozin; NCT01986881) trials., Results: The weighted analysis identified a population of 23,941,512 US adults from data on key inclusion criteria and information indicating a diagnosis of T2D. Of these, 4.1% met the criteria for EMPA-REG OUTCOME, 4.8% for VERTIS-CV, 8.8% for the CANVAS program, and 39.8% for the DECLARE-TIMI 58 trial., Conclusions: There were considerable differences in the proportions of US adults with T2D who met the eligibility criteria for these studies.The DECLARE-TIMI 58 trial criteria were the most generalizable to the US T2D population.

Objectives: The efficacy of dapagliflozin as add-on therapy to metformin has been assessed in randomized trials. However, its effectiveness has not been assessed in a US real-world setting., Methods: Electronic medical record (EMR) data were used to compare clinical outcomes among patients with type 2 diabetes (T2D) treated with dapagliflozin and metformin with or without other oral antidiabetic drugs (D + M ± OAD), versus metformin with at least 1 other OAD (M + OAD). Adult patients with T2D on these regimens from January 01, 2014, to February 28, 2015, were identified in a US EMR database, with the date of first prescription for dapagliflozin (D + M ± OAD) or other OAD (M + OAD) as the index date. Patients were observed for 12 months before the index date (baseline) and 12 months afterward (ie, follow-up). Patients in the M + OAD group were propensity score matched 1:1 to those in the D + M ± OAD group. Outcomes included change in glycated hemoglobin (A1C) level, weight, and systolic and diastolic blood pressures (SBP/DBP) from baseline to follow-up., Results: A total of 1093 patients receiving M + OAD were matched to 1093 patients receiving D + M ± OAD. Compared with those given M + OAD, patients given D + M ± OAD had a greater reduction in A1C level (mean, -1.0% vs -0.7%; P <.01), greater weight loss (-1.8 kg vs -0.7 kg, P <.01), and greater change in SBP (-3.6 mm Hg vs -0.1 mm Hg, P <.01) and DBP (-2.0 mm Hg vs -0.6 mm Hg, P <.01) from baseline to follow-up., Conclusions: In current US clinical practice, patients receiving D + M ± OAD had greater reductions in important clinical outcomes of T2D-A1C level, weight loss, and blood pressure-versus patients receiving M + OAD. This study supports the use of dapagliflozin as add-on therapy to metformin with or without other OADs for patients with T2D.

Objectives: Cardiovascular outcomes trials (CVOTs) for evaluating the safety of novel antidiabetic agents are required by the FDA. CVOTs vary in their design and inclusion criteria, making it difficult to evaluate their applicability to the general population. This study examined the proportion of adults eligible for 7 ongoing or completed glucagon-like peptide-1 receptor agonist (GLP-1 RA) CVOTs., Study Design: This cross-sectional, retrospective, cohort study compared data from the National Health and Nutrition Examination Survey (NHANES) with published eligibility criteria from GLP-1 RA CVOTs., Methods: Patient information on T2D status and other relevant characteristics were extracted from the 2009 to 2010 and the 2011 to 2012 NHANES. Weighted analyses of these data were used to calculate the numbers of adults with T2D in the US population who would have met eligibility criteria for enrollment in the following published or ongoing CVOTs: ELIXA (lixisenatide; NCT01147250), EXSCEL (Exenatide Study of Cardiovascular Event Lowering) (exenatide once weekly; NCT01144338), FREEDOM-CVO (exenatide via ITCA 650 miniature osmotic pump; NCT01455896), HARMONY Outcomes (albiglutide; NCT02465515), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results) (liraglutide; NCT01179048), REWIND (Researching Cardiovascular Events With a Weekly INcretin in Diabetes) (dulaglutide; NCT01394952), and SUSTAIN-6 (semaglutide; NCT01720446)., Results: The proportion of adults with T2D eligible for enrollment varied substantially among CVOTs (6.4%-47.2%); EXSCEL, which had a pragmatic study design, had the most generalizable inclusion criteria. More than 60% of patients with T2D would have qualified for enrollment into at least 1 GLP-1 RA CVOT., Conclusions: Most adults with T2D in the United States would have qualified for enrollment into at least 1 of the GLP-1 RA CVOTs evaluated. EXSCEL had the most generalizable eligibility criteria of these trials and ELIXA the least.

Objectives: The objective was to compare the use of low-dose liraglutide (LD-L) (Victoza) to the other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients without a type 2 diabetes (T2D) diagnosis in the post approval period for high-dose liraglutide (HD-L) (Saxenda), which is not indicated for T2D., Study Design: This was a retrospective, repeated cross-sectional, cohort study., Methods: Adult patients with T2D with more than 1 prescription for a GLP-1 RA in the Optum Humedica database between December 2014 and March 2016 were included. The proportions of patients without a T2D diagnosis who were prescribed L-DL versus the other GLP-1 RAs and within each cohort were computed. Logistic regression models estimated the predictive value of either treatment in those without a T2D diagnosis, controlling for multiple factors. To supplement these findings, administrative claims data were extracted from the Truven Health MarketScan database., Results: Analyses identified 11,245 patients prescribed LD-L and 4134 patients prescribed other GLP-1 RAs. For the entire study period, Humedica data revealed that patients without T2D accounted for 2.7% of the GLP-1 RA cohort and 17.5% of the LD-L cohort. Multivariable logistic regression analyses identified that patients receiving LD-L were more than 6 times likely to have no indication of T2D relative to patients taking other GLP-1 RAs. Claims data from MarketScan corroborated the Humedica results., Conclusions: In patients without a T2D diagnosis, LD-L use was significantly greater than that with other GLP-1 RAs within 6 months after approval of HD-L; differences persisted until the end of the study. Increased payer scrutiny of appropriate LD-L use is warranted.

Background: A previous factor analysis of Young Mania Rating Scale and Montgomery-Åsberg Depression Rating Scale items identified composite factors of depression, mania, sleep disturbance, judgment/impulsivity, and irritability/hostility as major components of psychiatric symptoms in acute mania or mixed episodes in a series of trials of antipsychotics. However, it is unknown whether these factors predict treatment outcome., Methods: Data from six double-blind, randomized, controlled clinical trials with aripiprazole in acute manic or mixed episodes in adults with bipolar I disorder were pooled for this analysis and the previously identified factors were examined for their value in predicting treatment outcome. Treatment efficacy was assessed for aripiprazole (n = 1,001), haloperidol (n = 324), lithium (n = 155), and placebo (n = 694) at baseline, days 4, 7, and 10, and then weekly to study end. Mean change in factor scores from baseline to week 3 was assessed by receiver operating characteristics curves for percentage factor change at day 4 and week 1., Results: Subjects receiving aripiprazole, haloperidol, and lithium significantly improved mania factor scores versus placebo. Factors most predictive of endpoint efficacy for aripiprazole were judgment/impulsivity at day 4 and mania at week 1. Optimal factor score improvement for outcome prediction was approximately 40% to 50%. Early efficacy predicted treatment outcome across all factors; however, response at week 1 was a better predictor than response at day 4., Conclusions: This analysis confirms clinical benefits in early treatment/assessment for subjects with bipolar mania and suggests that certain symptom factors in mixed or manic episodes may be most predictive of treatment response.