Impact of Insurance Status and Region on Angiotensin Receptor-Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations.

BACKGROUND: An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. OBJECTIVES: In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. METHODS: The authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines-Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. RESULTS: From 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. CONCLUSIONS: Among patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Estimating the clinical and budgetary impact of using angiotensin receptor neprilysin inhibitor as first line therapy in patients with HFrEF.

AIMS: Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first-line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. METHODS AND RESULTS: A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all-cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000-12 300 life years gained and 2600-4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112-195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. CONCLUSIONS: Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first-line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.

Effect of angiotensin receptor neprilysin inhibitor on physical activity in patients with heart failure with reduced ejection fraction, monitored by implantable electronic device home monitoring.

AIMS: Angiotensin receptor neprilysin inhibitor (ARNI) therapy is a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF), with significant improvement in mortality as well as morbidity and quality of life. However, maximal ARNI doses often result in hypotension. Recent studies with 'real world' experience suggest that lower doses of ARNI are as effective as higher doses.In order to evaluate the symptomatic effect of low-dose ARNI in HFrEF patients, we analyzed physical activity data obtained via home monitoring of patients with cardiac implantable electronic devices (CIEDs). METHODS: We retrospectively analyzed physical activity data obtained from HFrEF patients with CIED-active home monitoring during the years 2021-2022. Patients with ARNI therapy were further divided into subgroups according to the administered dose. Low-dose ARNI included doses of up to 24/26 mg sacubitril/valsartan daily. Intermediate dose and high dose included doses of 72/78-120/130 mg/day, and 144/156-194/206 mg/day, respectively. RESULTS: A total of 122 patients had home monitoring-compatible CIEDs and HFrEF during the study period. Sixty-four of these patients were treated with ARNI. Administration of low-dose ARNI resulted in a 20% increase in daily activity when compared with patients without ARNI treatment ( P  = 0.038). Change in physical activity of patients in the intermediate-dose and high-dose groups was not significant. Younger patients, patients with cardiac resynchronization therapy, and patients without diabetes mellitus were more physically active. CONCLUSION: Low-dose ARNI had a beneficial effect on physical activity in HFrEF patients. MH via CIED provided real-life objective data for patients' follow-up.

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Frailty and uptake of angiotensin receptor neprilysin inhibitor for heart failure with reduced ejection fraction.

BACKGROUND: Frail older adults may be less likely to receive guideline-directed medical therapy (GDMT)-renin-angiotensin blockers, beta-blockers, and mineralocorticoid receptor antagonists-for heart failure with reduced ejection fraction (HFrEF). We aimed to examine the uptake of angiotensin receptor neprilysin inhibitor (ARNI) and GDMT in frail older adults with HFrEF. METHODS: Using 2015-2019 Medicare data, we estimated the proportion of beneficiaries with HFrEF receiving ARNI and GDMT each year by frailty status, defined by a claims-based frailty index. Logistic regression was used to identify clinical characteristics associated with ARNI initiation. Cox proportional hazards regression was used to examine the association of GDMT use in 2015 and death or heart failure hospitalization in 2016-2019. RESULTS: Among 147,506-180,386 beneficiaries with HFrEF (mean age: 77 years; 27% women; 42.6-49.1% frail) in 2015-2019, the proportion of patients receiving ARNI increased in both non-frail (0.4%-16.4%) and frail (0.3%-13.7%) patients (p for yearly-trend-by-frailty = 0.970). Among those not receiving a renin-angiotensin system blocker, patients with age ≥ 85 years (odds ratio [95% CI], 0.89 [0.80-0.99]), dementia (0.88 [0.81-0.96]), and frailty (0.87 [0.81-0.94]) were less likely to initiate ARNI. The proportion of patients receiving all 3 GDMT classes increased in non-frail patients (22.0%-27.0%) but changed minimally in frail patients (19.6%-21.8%). Regardless of frailty status, treatment with at least 1 class of GDMT was associated with lower death or heart failure hospitalization than no GDMT medications (hazard ratio [95% CI], 0.94 [0.91-0.97], 0.92 [0.89-0.94], 0.94 [0.91-0.97] for 1, 2, and 3 classes, respectively). CONCLUSIONS: Our results suggest an evidence-practice gap in the use of ARNI and GDMT in Medicare beneficiaries with HFrEF, particularly those with frailty. Efforts to narrow this gap are needed to reduce the burden of HFrEF in older adults.

Quality of Care and Clinical Outcomes for Patients With Heart Failure at Hospitals Caring for a High Proportion of Black Adults: Get With The Guidelines-Heart Failure Registry.

Importance: Black adults with heart failure (HF) disproportionately experience higher population-level mortality than White adults with HF. Whether quality of care for HF differs at hospitals with high proportions of Black patients compared with other hospitals is unknown. Objective: To compare quality and outcomes for patients with HF at hospitals with high proportions of Black patients vs other hospitals. Design, Setting, and Participants: Patients hospitalized for HF at Get With The Guidelines (GWTG) HF sites from January 1, 2016, through December 1, 2019. These data were analyzed from May 2022 through November 2022. Exposures: Hospitals caring for high proportions of Black patients. Main Outcomes and Measures: Quality of HF care based on 14 evidence-based measures, overall defect-free HF care, and 30-day readmissions and mortality in Medicare patients. Results: This study included 422 483 patients (224 270 male [53.1%] and 284 618 White [67.4%]) with a mean age of 73.0 years. Among 480 hospitals participating in GWTG-HF, 96 were classified as hospitals with high proportions of Black patients. Quality of care was similar between hospitals with high proportions of Black patients compared with other hospitals for 11 of 14 GWTG-HF measures, including use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitors for left ventricle systolic dysfunction (high-proportion Black hospitals: 92.7% vs other hospitals: 92.4%; adjusted odds ratio [OR], 0.91; 95% CI, 0.65-1.27), evidence-based ß-blockers (94.7% vs 93.7%; OR, 1.02; 95% CI, 0.82-1.28), angiotensin receptor neprilysin inhibitors at discharge (14.3% vs 16.8%; OR, 0.74; 95% CI, 0.54-1.02), anticoagulation for atrial fibrillation/flutter (88.8% vs 87.5%; OR, 1.05; 95% CI, 0.76-1.45), and implantable cardioverter-defibrillator counseling/placement/prescription at discharge (70.9% vs 71.0%; OR, 0.75; 95% CI, 0.50-1.13). Patients at high-proportion Black hospitals were less likely to be discharged with a follow-up visit made within 7 days or less (70.4% vs 80.1%; OR, 0.68; 95% CI, 0.53-0.86), receive cardiac resynchronization device placement/prescription (50.6% vs 53.8%; OR, 0.63; 95% CI, 0.42-0.95), or an aldosterone antagonist (50.4% vs 53.5%; OR, 0.69; 95% CI, 0.50-0.97). Overall defect-free HF care was similar between both groups of hospitals (82.6% vs 83.4%; OR, 0.89; 95% CI, 0.67-1.19) and there were no significant within-hospital differences in quality for Black patients vs White patients. Among Medicare beneficiaries, the risk-adjusted hazard ratio (HR) for 30-day readmissions was higher at high-proportion Black vs other hospitals (HR, 1.14; 95% CI, 1.02-1.26), but similar for 30-day mortality (HR 0.92; 95% CI,0.84-1.02). Conclusions and Relevance: Quality of care for HF was similar across 11 of 14 measures at hospitals caring for high proportions of Black patients compared with other hospitals, as was overall defect-free HF care. There were no significant within-hospital differences in quality for Black patients vs White patients.

Risk of Acute Kidney Injury Among Older Adults With Heart Failure and With Reduced Ejection Fraction Treated With Angiotensin-Neprilysin Inhibitor vs Renin-Angiotensin System Inhibitor in Routine Clinical Care.

BACKGROUND: The acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis). METHODS: We conducted a cohort study using U.S. Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: We included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%-3.1%) among RASi initiators and 2.7% (2.2%-3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%-7.1%) and 6.1% (5.2%-7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72-1.16) for the primary outcome and 0.92 (95% CI: 0.79-1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis. CONCLUSIONS: Among a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.

Evaluación clínica y económica del uso de sacubitrilo/valsartán en la insuficiencia cardiaca aguda / Clinical and economic evaluation of the use of sacubitril/valsartan in acute heart failure

CONTEXTO: La ICA se define como la aparición rápida o gradual de signos o síntomas de IC, lo bastante graves para que el paciente necesite atención médica urgente que lleva al ingreso hospitalario no planificado o a la atención en el servicio de urgencias. Los pacientes con ICA requieren evaluación urgente y el inicio o la intensificación del tratamiento, incluidos fármacos intravenosos y procedimientos. La ICA es la mayor causa de hospitalizaciones de personas de más de 65 años y se asocia con tasas elevadas de muerte y reingreso. La mortalidad hospitalaria varía entre el 4 y el 10%. La mortalidad al año después del alta puede ser del 25 al 30%, con tasa de reingreso superior a 45%. La ICA se puede presentar como una primera manifestación de la IC (de novo) o, más frecuentemente, como consecuencia de una descompensación aguda de la IC crónica. Comparados con los pacientes con descompensación aguda de la IC crónica, los pacientes con IC de nueva aparición pueden tener una tasa más alta de mortalidad hospitalaria, pero las tasas de mortalidad y reingresos después del alta son más bajas. Factores extrínsecos pueden precipitar, pero no causar la ICA en pacientes con disfunción cardiaca preexistente. La gravedad clínica y la evolución en el hospital están determinadas por la compleja interacción entre los factores precipitantes, el sustrato cardiaco y las comorbilidades del paciente. El proceso diagnóstico de la ICA comienza en el momento del primer contacto médico y continúa durante las fases iniciales, a efectos de identificar la presentación clínica, diagnosticar y tratar en el momento oportuno las posibles causas, los factores desencadenantes y las comorbilidades que pudieran suponer riesgo para la vida. Además de los signos clínicos, el proceso diagnóstico incluye ECG y la ecocardiografía, siempre que sea posible. Pueden hacerse pruebas adicionales como radiografía de tórax y ecografía pulmonar para confirmar el diagnóstico de ICA. Se deben medir las concentraciones plasmáticas de péptido natriurético (BNP, NT-proBNP o MR-proANP) cuando el diagnóstico sea incierto. Las concentraciones normales de péptido natriurético hacen poco probable el diagnóstico de ICA. Se pueden describir cuatro presentaciones clínicas con algunos solapamientos entre ellas: 1. Insuficiencia cardiaca en descompensación aguda 2. Edema pulmonar agudo 3. Insuficiencia ventricular derecha aislada 4. Choque cardiogênico. MÉTODOS: Para dar respuesta a la pregunta propuesta, se realizó una búsqueda sistemática en las bases de datos de Pubmed, CENTRAL (Cochrane), y de la Biblioteca Médica de Salud (BVS), utilizando tesauros (MeSH), así como términos libres sin limitaciones por edad, sexo, año de publicación, tipo de estudio, ni idioma. Se utilizan las siguientes palabras clave: acute heart failure, acute descompensated heart failure, insuficiencia cardiaca aguda, insuficiencia cardiaca crónica descompensada, LCZ696, ARNi, sacubitrilo, valsartán, sacubitrilo/valsartán. Para los aspectos económicos se utilizaron los siguientes términos: acute heart failure, sacubitrilo/valsartán, cost analysis, cost effectiveness, cost utility, cost benefit, economic evaluation, budget impact, health technology assessment en las bases de datos de Pubmed, y BVS. RESULTADOS: Se evaluaron tanto de forma conjunta como separada los desenlaces de mortalidad y rehospitalización. En su evaluación en conjunto, la mortalidad por todas las causas o rehospitalización por insuficiencia cardiaca o implantación de dispositivo de asistencia ventricular o el ingreso a lista de espera para trasplante cardiaco, S/V fue superior a enalapril en pacientes adultos con insuficiencia cardiaca aguda (de novo o con empeoramiento de insuficiencia cardiaca crónica) con fracción de eyección ≤40%, con diferencia estadísticamente significativa. De igual forma, al analizar el desenlace compuesto simplificado de muerte por causas cardiovasculares o rehospitalización por insuficiencia cardiaca, en la misma población, mostró superioridad frente a enalapril, sin importar la dosis alcanzada, de acuerdo a los resultados de 2 ensayos clínicos y 1 estudio de cohorte. Al realizar el análisis por subpoblaciones, de acuerdo a un ensayo clínico, en pacientes con insuficiencia cardiaca crónica descompensada o con empeoramiento, no hubo significancia estadística. De acuerdo a un ensayo clínico, hay ciertos factores agravantes que aumentan el riesgo de mortalidad cardiovascular y rehospitalización por insuficiencia cardiaca, estos son: admisión a terapia intensiva en el primer internamiento, nivel de NT-proBNP >2701 pg/mL, puntuación de congestión ≥4 y presentar ≥1 hospitalización por insuficiencia cardiaca en el año previo. Lo cual se confirma en otro ensayo clínico que demostró que los pacientes con un nivel de NT-proBNP alto presentan un riesgo de rehospitalización por insuficiencia cardiaca o muerte cardiovascular mayor que los que presentan niveles bajos. De forma similar, aquellos pacientes que tuvieron descenso de NT-proBNP secundario a S/V mostraron un menor riesgo de rehospitalización por insuficiencia cardiaca o muerte cardiovascular. De igual forma, se observó que los pacientes con insuficiencia cardiaca de novo, o näive a tratamiento con iECA/ARA, presentaron mejores respuestas con S/V, al compararse contra enalapril, al reducir el riesgo del desenlace compuesto muerte cardiovascular y rehospitalización por insuficiencia cardiaca. El efecto benéfico de S/V sobre el riesgo de hospitalización por todas las causas y de muerte, así como hospitalización y muerte cardiovascular no difirió entre los pacientes con ICA con distintas fracciones de eyección (≤40% o >40%). Por otra parte, se documentó que los pacientes con enfermedad pulmonar obstructiva crónica, o insuficiencia renal, tuvieron los peores resultados en mortalidad por todas las causas, mortalidad cardiovascular o en el desenlace compuesto de mortalidad cardiovascular o rehospitalización por insuficiencia cardiaca. CONCLUSIONES: Se realizó un análisis que demuestra la eficacia de Sacubitrilo/Valsartán en la insuficiencia cardiaca aguda con fracción de eyección reducida, ya que disminuye la tasa de rehospitalización y la mortalidad a mediano plazo. Se tiene que considerar sus posibles efectos adversos (hipotensión sintomática) al utilizarse en pacientes con cifras tensionales bajas y debe de mantenerse la farmacovigilancia debido a los reportes de demencia en su uso crónico. Se analizaron tres estudios de costo efectividad para medir el impacto económico por la introducción de Sacubitrilo-Valsartán desde la perspectiva del sistema de salud; mientras que en el estudio de Perera, (2019) (realizado en Australia), S/V no fue costo efectivo en comparación con enalapril debido a los altos costos; en los estudios de Krittayaphong, (2021) y Tianyang (2023) realizados en China y Tailandia, respectivamente, S/V resultó ser una opción costo-efectiva en comparación con enalapril, estos resultados pueden ser debido a los bajos precios de compra y a los parámetros clínicos locales, por lo que, los resultados dependen en gran medida de algunas variables como la mortalidad, costos y solo son aplicables en los países en donde se realizaron los estudios (China, Tailandia y Australia).

Medication Trajectory and Treatment Patterns in Medicare Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Although a worsening heart failure event (WHFE) is associated with poor outcomes in patients with heart failure with reduced ejection fraction (HFrEF), it is unclear how guideline-directed medical therapy (GDMT) is used in this population compared to those without WHFEs. This study evaluated treatment patterns in patients with HFrEF, both with and without WHFEs. METHODS: A retrospective study using 100% Medicare Fee-For-Service claims identified beneficiaries with HFrEF, stratified by those with and without WHFEs (defined as hospitalization due to HF or outpatient intravenous diuretic use). The use of GDMT for HFrEF before and after WHFEs and adherence were assessed in patients who were prescribed and initiated GDMT. Logistic regression identified patients' characteristics associated with medication nonadherence. RESULTS: Of 353,642 patients with HFrEF, 31.4% had a WHFE. Although there was no overall change in the treatment trajectory of patients without WHFEs, GDMT use in patients with WHFEs intensified within the first 3 months of a WHFE, but the intensification was not sustained in subsequent months. From 0-3 months pre-WHFE to 0-3 months post-WHFE, the proportion of patients receiving dual (41%-48%) and triple-therapy (4%-12%) increased, followed by a decline to pre-WHFE rates. The 1-year adherence rates for those with and without WHFEs were 67.9% vs 73.3% for beta-blockers; 59.1% vs 70.9% for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists; 53.9% vs 61.3% for angiotensin receptor-neprilysin inhibitors; and 49.2% vs 59.3% for mineralocorticoid receptor antagonists. WHFE, age < 65 years, Black race, asthma, chronic kidney disease, and depression were associated with nonadherence to medications. Asians and Hispanics were less adherent to some medication classes. CONCLUSIONS: This study demonstrated underuse of GDMT for patients with HFrEF with or without WHFEs. Although there was a treatment escalation within 3 months following WHFE, it was not sustained thereafter.

Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Critical evaluation of the utility of pre- and post-therapy immunophenotypes in assessment of measurable residual disease in B-ALL.

Measurable residual disease (MRD) is an important parameter to predict outcome in B-cell acute lymphoblastic leukemia (B-ALL). Two different approaches have been used for the assessment of MRD by multiparametric flow cytometry that include the "Leukemia Associated Aberrant Immunophenotype (LAIP)" and "Difference from Normal (DFN)" approach. In this retrospective study, we analyzed 539 samples obtained from 281 patients of which 258 were paired samples and the remaining 23 samples were from post-induction time point only, to explore the utility of baseline immunophenotype (IPT) for MRD assessment. Single-tube 10-color panel was used both at diagnosis and MRD time points. Out of 281 patients, 31.67% (n = 89) were positive and 68.32% (n = 192) were negative for MRD. Among 258 paired diagnostic and follow-up samples, baseline IPT was required in only 9.31% (24/258) cases which included cases with hematogone pattern and isolated dim to negative CD10 expression patterns. Comparison of baseline IPT with post-induction MRD positive samples showed a change in expression of at least one antigen in 94.04% cases. Although the immunophenotypic change in expression of various antigens is frequent in post-induction samples of B-ALL, it does not adversely impact the MRD assessment. In conclusion, the baseline IPT is required in less than 10% of B-ALL, specifically those with hematogone pattern and/or dim to negative expression of CD10. Hence, a combination of DFN and LAIP approach is recommended for reliable MRD assessment.

Effectiveness of angiotensin-neprilysin inhibitor treatment versus renin-angiotensin system blockade in older adults with heart failure in clinical care.

OBJECTIVE: To evaluate the effectiveness of angiotensin receptor-neprilysin inhibitor (ARNI) versus renin-angiotensin system (RAS) blockade alone in older adults with heart failure with reduced ejection fraction (HFrEF). METHODS: We conducted a cohort study using US Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥65 years were identified in two cohorts: (1) initiators of ARNI or RAS blockade alone (ACE inhibitor, ACEI; or angiotensin receptor blocker, ARB) and (2) switchers from an ACEI to either ARNI or ARB. HR with 95% CI from Cox proportional hazard regression and 1-year restricted mean survival time (RMST) difference with 95% CI were calculated for a composite outcome of time to first worsening heart failure event or all-cause mortality after adjustment for 71 pre-exposure characteristics through propensity score fine-stratification weighting. All analyses of initiator and switcher cohorts were conducted separately and then combined using fixed effects. RESULTS: 51 208 patients with a mean age of 76 years were included, with 16 193 in the ARNI group. Adjusted HRs comparing ARNI with RAS blockade alone were 0.92 (95% CI 0.84 to 1.00) among initiators and 0.79 (95% CI 0.74 to 0.85) among switchers, with a combined estimate of 0.84 (95% CI 0.80 to 0.89). Adjusted 1-year RMST difference (95% CI) was 4 days in the initiator cohort (-1 to 9) and 12 days (8 to 17) in the switcher cohort, resulting in a pooled estimate of 9 days (6 to 12) favouring ARNI. CONCLUSION: ARNI treatment was associated with lower risk of a composite effectiveness endpoint compared with RAS blockade alone in older adults with HFrEF.

Therapeutic Assessment of Combination Therapy with a Neprilysin Inhibitor and Angiotensin Type 1 Receptor Antagonist on Angiotensin II-Induced Atherosclerosis, Abdominal Aortic Aneurysms, and Hypertension.

Combined neprilysin (NEP) inhibition (sacubitril) and angiotensin type 1 receptor (AT1R) antagonism (valsartan) is used in the treatment of congestive heart failure and is gaining interest for other angiotensin II (AngII)-related cardiovascular diseases. In addition to heart failure, AngII promotes hypertension, atherosclerosis, and abdominal aortic aneurysms (AAAs). Similarly, NEP substrates or products have broad effects on the cardiovascular system. In this study, we examined NEP inhibition (with sacubitril) and AT1R antagonism (with valsartan) alone or in combination on AngII-induced hypertension, atherosclerosis, or AAAs in male low-density lipoprotein receptor-deficient mice. Preliminary studies assessed drug delivery via osmotic minipumps for simultaneous release of sacubitril and/or valsartan with AngII over 28 days. Mice were infused with AngII (1000 ng/kg per minute) in the absence (vehicle) or presence of sacubitril (1, 6, or 9 mg/kg per day), valsartan (0.3, 0.5, 1, 6, or 20 mg/kg per day), or the combination thereof (1 and 0.3, or 9 or 0.5 mg/kg per day of sacubitril and valsartan, respectively). Plasma AngII and renin concentrations increased 4-fold at higher valsartan doses, indicative of removal of AngII negative feedback on renin. Sacubitril doubled plasma AngII concentrations at lower doses (1 mg/kg per day). Valsartan dose-dependently decreased systolic blood pressure, aortic atherosclerosis, and AAAs of AngII-infused mice, whereas sacubitril had no effect on atherosclerosis or AAAs but reduced blood pressure of AngII-infused mice. Combination therapy with sacubitril and valsartan did not provide additive benefits. These results suggest limited effects of combination therapy with NEP inhibition and AT1R antagonism against AngII-induced hypertension, atherosclerosis, or AAAs. SIGNIFICANCE STATEMENT: The combination of valsartan (angiotensin type 1 receptor antagonist) and sacubitril (neprilysin inhibitor) did not provide benefit above valsartan alone on AngII-induced hypertension, atherosclerosis, or abdominal aortic aneurysms in low-density lipoprotein receptor-deficient male mice. These results do not support this drug combination in therapy of these AngII-induced cardiovascular diseases.

Show Me the Money: Patients' Perspectives on a Decision Aid for Sacubitril/Valsartan Addressing Out-of-Pocket Cost.

BACKGROUND: Out-of-pocket medication costs for patients who have heart failure with reduced ejection fraction may be an important part of shared decision-making, but cost has generally been excluded from clinical discussions. This study reports patients' perspectives on a decision aid for sacubitril/valsartan that explicitly addresses out-of-pocket costs. METHODS: Structured, in-depth interviews were conducted with 20 patients with heart failure with reduced ejection fraction from 2 medical centers to elicit their views on a publicly available decision aid for sacubitril/valsartan that explicitly incorporates considerations related to out-of-pocket costs. Qualitative descriptive analysis was conducted. RESULTS: Key themes identified were general enthusiasm for decision aids for medication decisions, openness on the part of patients to incorporation of cost into decision-making and the decision aid, requests for greater specificity regarding patient-specific cost, and challenges communicating evidence of benefit in a way that allows patients to make cost-benefit analyses for themselves. Patients also raised questions regarding logistical challenges of incorporating a decision aid into the normal clinical and decision-making workflow. CONCLUSIONS: Patients were receptive to the inclusion of out-of-pocket cost as relevant in a decision aid for sacubitril/valsartan. Key challenges to effective integration of cost in these decisions include developing mechanisms for acquiring reliable patient-specific cost estimates and addressing patients' difficulties (and sometimes skepticism) applying trial evidence to their own situation. In addition, implementation strategies are important to develop to facilitate decision aid integration for routine medical decisions into clinic workflow.

Conflicting Perspectives on the Value of Neprilysin Inhibition in Heart Failure Revealed During Development of a Decision Aid Focusing on Patient Costs for Sacubitril/Valsartan.

BACKGROUND: Despite concerns about rising costs in health care, cost is rarely an issue discussed by patients and clinicians when making treatment decisions in a clinical setting. This study aimed to understand stakeholder perspectives on a patient decision aid (PtDA) meant to help patients with heart failure choose between a generic and relatively low-cost heart failure medication (ACE [angiotensin-converting enzyme] inhibitor or angiotensin II receptor blocker) and a newer, but more expensive, heart failure medication (angiotensin II receptor blocker neprilysin inhibitor). METHODS AND RESULTS: Feedback on the PtDA was solicited from 26 stakeholders including patients, clinicians, and the manufacturer. Feedback was recorded and discussed among development team members until consensus regarding both the interpretation of the data and the appropriate changes to the PtDA was reached. Stakeholders found the PtDA sufficient in clarifying the different treatment options for heart failure. However, patients, physicians, and the manufacturer had different opinions on the importance of highlighting cost in a PtDA. Patients indicated issues of cost were crucial to the decision while physicians and manufacturers expressed that the cost issue was secondary and should be de-emphasized. CONCLUSIONS: The stratified perspectives on the role of cost in medical decision-making expressed by our participants underscore the importance and challenge of having clear, frank discussions during clinic visits about treatment cost and perceived value.

Angiotensin Receptor Neprilysin Inhibitors-2019 Update.

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.

Cost-Effectiveness of Switching Patients With Heart Failure and Reduced Ejection Fraction to Sacubitril/Valsartan: The Australian Perspective.

BACKGROUND: The cost-effectiveness, from the Australian health care perspective, of switching patients with heart failure and reduced ejection fraction (HFREF) stable on angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) to the angiotensin receptor neprilysin inhibitor (ARNi) sacubitril/valsartan is unclear. We sought to assess the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with HFREF in the contemporary Australian setting. METHODS: We developed a Markov model with two health states ('Alive' and 'Dead') to assess the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with HFREF. Model subjects were 63 years of age at entry and had simulated follow-up over 20 years. Transition probabilities were derived from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) study. Costs and utility data were derived from published sources. All costs and effects were discounted at an annual rate of 5% and are presented in Australian dollars. Sensitivity analyses were undertaken to test variability in key data inputs. RESULTS: In the base-case analysis, sacubitril/valsartan was found to reduce non-fatal heart failure hospitalisations and cardiovascular deaths, with numbers-needed-to-treat over a 20-year period of 40 and 27, respectively. The use of sacubitril/valsartan led to an additional 6 months of life gained per patient, translating to A$27,954 per years of life saved (YoLS) and A$40,513 per quality-adjusted-life-years (QALY) gained. The results of the sensitivity analyses indicated that the results were robust. CONCLUSIONS: Our analysis supports switching HFREF patients on ACE inhibitor or ARB to sacubitril/valsartan.

Artifactual Kappa Light Chain Restriction of Marrow Hematogones: A Potential Diagnostic Pitfall in Minimal Residual Disease Assessment of Plasma Cell Myeloma Patients on Daratumumab.

BACKGROUND: Daratumumab (DARA) is a humanized Immunoglobulin G(IgG)1-kappa monoclonal antibody against CD38 antigen that is shown to improve outcomes in relapsed/refractory plasma cell myeloma (PCM) patients. Since CD38 is expressed by different hematopoietic elements, DARA has the potential to interfere with flow cytometric assessment of bone marrow specimens. METHODS: Flow cytometric analysis of bone marrow samples from 10 PCM on DARA and 5 control samples was performed using two different antibody panels. RESULTS: Bone marrow samples from PCM patients on DARA exhibited a population of CD19+ CD10+ B-lymphoid cells with kappa light chain restriction. Further morphological and immunophenotypic studies suggested that this population represents marrow hematogones. Marrow hematogones from control samples showed normal immunophenotypic profiles. CONCLUSION: DARA on the surface of hematogones interferes with flow cytometric clonality study leading to artifactual kappa light chain restriction, which can result in false interpretation of a concurrent clonal B-cell proliferation. In the era of rapidly growing list of therapeutic monoclonal antibodies, flow cytometry pathologists should be aware of potential interferences to avoid misdiagnosis. © 2019 International Clinical Cytometry Society.