Cost-Effectiveness of Medical Therapy for Heart Failure With Mildly Reduced and Preserved Ejection Fraction.

BACKGROUND: Three medications are now guideline-recommended treatments for heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF), however, the cost-effectiveness of these agents in combination has yet to be established. OBJECTIVES: The purpose of this study was to determine the cost-effectiveness of mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium glucose co-transporter 2 inhibitors (SGLT2is) in individuals with HFmrEF/HFpEF. METHODS: Using a 3-state Markov model, we performed a cost-effectiveness study using simulated cohorts of 1,000 patients with HFmrEF and HFpEF. Treatment with 1-, 2-, and 3-drug combinations was modeled. Based on a United States health care sector perspective, outcome data was used to calculate incremental cost-effectiveness ratios (ICERs) in 2023 United States dollars based on a 30-year time horizon. RESULTS: Treatment with MRA, MRA+SGLT2i, and MRA+SGLT2i+ARNI therapy resulted in an increase in life years of 1.04, 1.58, and 1.80 in the HFmrEF subgroup, respectively, and 0.99, 1.54, and 1.77 in the HFpEF subgroup, respectively, compared with placebo. At a yearly cost of $18, MRA therapy resulted in ICERs of $10,000 per quality-adjusted life year (QALY) in both subgroups. The ICER for the addition of SGLT2i therapy ($4,962 per year) was $113,000 per QALY in the HFmrEF subgroup and $141,000 in the HFpEF subgroup. The addition of ARNI therapy ($5,504 per year) resulted in ICERs >$250,000 per QALY in both subgroups. If SGLT2i and ARNI were available at generic pricing the ICERs become <$10,000 per QALY in both EF subgroups. Outcomes were highly sensitive to assumed benefit in cardiovascular death. CONCLUSIONS: For patients with heart failure, MRA was of high value, SGLT2i was of intermediate value, and ARNI was of low value in both HFmrEF and HFpEF subgroups. For patients with HFmrEF/HFpEF increased use of MRA and SGLT2i therapies should be encouraged and be accompanied with efforts to lower the cost of SGLT2i and ARNI therapies.

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.

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).

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.

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.

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.

Eficacia de sacubitrilo/valsartán en pacientes con insuficiencia cardiaca crónica de fracción de eyección reducida grado funcional II-IV recibiendo terapia médica óptima a dosis máxima tolerable por un tiempo mínimo de seis meses que se encuentren hospitalizados por falla cardiaca descompensada / Efficacy of sacubitril/valsartan in patients with chronic heart failure with reduced ejection fraction functional grade II-IV receiving optimal medical therapy at the maximum tolerable dose for a minimum of six months who are hospitalized for decompensated heart failure

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de sacubitrilo/valsartán en pacientes con insuficiencia cardiaca crónica (ICC) con fracción de eyección ventricular izquierda reducida (FEVI-r) de clase funcional NYHA II a IV, en terapia médica óptima (TMO) a dosis máxima tolerable (DMT) por mínimo tres meses que se encuentren hospitalizados por falla cardiaca descompensada. El sacubitrilo/valsartán ya ha sido evaluado por el IETSI a través del Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 015-SDEPFyOTS-DETS-IETSI-2018 "Eficacia y seguridad de sacubitrilo/valsartán en pacientes con insuficiencia cardiaca CF II-IV, fracción de eyección disminuida, sintomático, y en terapia médica óptima". El IETSI no aprobó el uso de sacubitrilo/valsartán debido a que un único ensayo clínico aleatorizado, el estudio PARADIGM-HR, presentó múltiples limitaciones metodológicas que finalmente no lograron demostrar superioridad en eficacia y seguridad en comparación con la terapia médica óptima. La falla cardiaca o insuficiencia cardiaca de fracción de eyección reducida es un síndrome clínico que se manifiesta sintomáticamente cuando hay un desorden cardiaco funcional o estructural que impide que el ventrículo pueda llenarse o eyectar sangre al resto del cuerpo. Por consenso, se habla de falla cardiaca con fracción de eyección (FE) reducida cuando hay una FE del ventrículo izquierdo menor a 40 %. Para clasificar la severidad de falla cardiaca con respecto a la presencia o no de síntomas, se utiliza la clasificación de clase funcional (CF) NYHA; es así, como una CF de I se da cuando el paciente es asintomático y una CF de II a IV cuando el paciente se encuentra, en diferentes niveles, sintomático. Una descompensación por falla cardiaca es un síndrome clínico agudo que por su potencial riesgo de mortalidad conduce a que el paciente se hospitalice o acuda a al servicio de emergencia. En pacientes con falla cardiaca crónica, la descompensación puede ocurrir sin un precipitante conocido, pero con mayor frecuencia se da por infecciones, hipertensión arterial no controlada, trastornos rítmicos cardiacos (taquicardia, bradicardia) o la no adherencia a la dieta o tratamiento. El manejo de la descompensación aguda por falla cardiaca no incluye los medicamentos para el manejo de falla cardiaca crónica (Inhibidores de la encima convertidora de angiotensina [IECA], antagonistas de los receptores de la angiotensina II [ARA-II], beta-bloqueadores, antagonistas de receptores de mineralocorticoides). El manejo de falla cardiaca crónica de FE reducida se realiza con la inhibición de los tres ejes del sistema renina-angiotensina-aldosterona. De esta manera, el eje de la renina es manejado con los beta-bloqueadores; el eje de la angiotensina con IECA (o ARA-II en caso de haber intolerancia a los IECA); y el eje de aldosterona con los antagonistas de aldosterona como la espironolactona. El Petitorio Farmacológico de EsSalud cuenta con diferentes opciones para cada grupo de medicamentos del manejo de falla cardiaca. No obstante, existen pacientes que a pesar de encontrarse en terapia medica óptima a máximas dosis tolerables con las opciones disponibles en la institución presentan falla cardiaca descompensada con requerimiento de hospitalización. Así, surge la necesidad de evaluar otras opciones de tratamiento para el manejo de la falla cardiaca crónica. METODOLOGÍA: Para responder la pregunta PICO de investigación (Tabla 1) se realizó una búsqueda bibliográfica sistemática abierta en las bases de datos MEDLINE vía PubMed, Cochrane Database (ambas estrategias de búsqueda en el Anexo 1) y www.clinicaltrials.gov. Adicionalmente se realizó una búsqueda de guías de práctica clínica y evaluaciones de tecnologías sanitarias en las páginas web de la Asociación Americana del Corazón (AHA, por sus siglas en inglés), Colegio Americano de Cardiología (ACC, por sus siglas en inglés), Sociedad Cardiovascular Canadiense (CCS, por sus siglas en inglés), Sociedad Europea de Cardiología (ESC, por sus siglas en inglés), Red Escocesa de Guías Intercolegiales (SIGN, por sus siglas en inglés), Instituto Nacional de Salud y Cuidados de Excelencia (NICE, por sus siglas en inglés), Agencia Canadiense de Drogas y Tecnologías en Salud (CADTH, por sus siglas en inglés), Consorcio Escocés de Medicamentos (SMC, por sus siglas en inglés) y el Instituto de Revisiones Clínicas y Económicas (ICER, por sus siglas en inglés). Se priorizó la selección de guías de práctica clínica (GPC), evaluaciones de tecnología sanitaria (ETS), revisiones sistemáticas con meta-análisis y ensayos clínicos aleatorizados (ECA) que permitieran responder la pregunta PICO formulada. RESULTADOS: En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En EsSalud, se cuenta con medicamentos de las tres clases necesarias para la terapia médica óptima de falla cardiaca de fracción de eyección reducida. Estos son los IECA (o ARA-II en caso de intolerancia a IECA), los beta-bloqueadores, y los antagonistas de aldosterona. El IETSI ya ha elaborado una evaluación de sacubitrilo/valsartán el cual se encuentra publicado como Dictamen Preliminar de Evaluación de Tecnología Sanitaria No. 15-SDEPFYOTS-DETS-IETSI-2018. En este dictamen no se aprueba el uso de esta tecnología sanitaria en el contexto de un paciente ambulatorio con falla cardiaca con fracción de eyección reducida, CF NYHA II-IV, recibiendo terapia médica óptima. El presente dictamen se realiza por tratarse, según los especialistas, de una población diferente al ser pacientes con falla cardiaca crónica con fracción de eyección reducida, sintomáticos (clase funcional NYHA II a IV), a pesar de recibir terapia médica óptima a dosis máxima tolerable por un tiempo mínimo de seis meses que se encuentren hospitalizados debido a falla cardiaca descompensada. Se seleccionaron y revisaron cuatro guías de práctica clínica (AHA/ACC 2017, CCS 2016, ESC 2016, SIGN-147) las cuales no son consistentes en sus recomendaciones a favor de sacubitrilo/valsartán. Por un lado, recomiendan su uso en remplazo de los IECA (o ARA-II en caso de intolerancia a IECA) por considerarlo de mayor beneficio. Por otro lado, recomiendan su uso sin preferencia como una alternativa a los IECA (o ARA-II en caso de intolerancia a IECA). Adicionalmente se incluyeron tres evaluaciones de tecnología sanitaria (NICE 2016, CADTH 2016 y ICER 2015) las cuales recomiendan el uso de sacubitrilo/valsartán en reemplazo de IECA (o ARA-II en caso de intolerancia a IECA). Tanto las guías de práctica clínica como las evaluaciones de tecnologías sanitarias se realizan en el contexto de un paciente ambulatorio, diferente a la población de la pregunta PICO del presente dictamen. No se encontraron revisiones sistemáticas ni ensayos clínicos que respondan la pregunta PICO del presente dictamen. A la fecha, la seguridad y tolerabilidad del uso de sacubitrilo/valsartán continúa siendo incierta. Existen varios estudios registrados en la página web clinicaltrials.gov que a pesar de haber culminado aun no tienen una publicación de sus resultados en una revista donde se realice una revisión por pares. Ante la falta de una opción terapéutica y de evidencia científica para la población de la pregunta PICO del presente dictamen, se acude a la opinión de médicos especialistas en cardiología. Los especialistas opinan que en el escenario de un paciente con falla cardiaca crónica de fracción de eyección reducida (FEVI<40%), clase funcional NYHA II a IV y que se encuentra hospitalizado por falla cardiaca descompensada a pesar de estar en terapia médica óptima a dosis máxima tolerable por un tiempo mínimo de seis meses, el uso de sacubitrilo/valsartán podría brindar beneficio clínico al paciente. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación - IETSI, aprueba el uso de sacubitrilo/valsartán en reemplazo de IECA (o ARA-II en caso de intolerancia a IECA) para el manejo de los pacientes con falla cardiaca crónica con fracción de eyección reducida de clase funcional NYHA II-IV, en terapia médica óptima por un tiempo mínimo de seis meses y que se encuentren hospitalizados por falla cardiaca descompensada. La vigencia del presente Dictamen Preliminar es de un año a partir de la fecha de publicación y está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Neprilysin Inhibitors: Filling a Gap in Heart Failure Management, Albeit Amidst Controversy and at a Significant Cost.

Dual angiotensin and neprilysin inhibition using the combination drug sacubitril-valsartan has ushered in a new era in the treatment of heart failure (HF). The randomized controlled PARADIGM-HF trial, which randomized 8399 patients with HF to enalapril or sacubitril-valsartan, showed a 20% reduction in mortality and HF hospitalization with the new drug. This has been heralded as a step toward filling a crucial gap in HF management by providing strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin-angiotensin system alone in stable patients with chronic HF as it negates the deleterious effects of angiotensin while concomitantly augmenting the beneficial effects of the endogenous natriuretic peptide system. This new therapy is costly, and other confirmatory studies have been lacking for over 2 years since its approval by major regulatory authorities. As such, controversy and heated discussions have amassed, as has detailed information from a plethora of secondary analyses of this pivotal trial about the pros and cons of this promising new therapeutic strategy in HF management. The aim of this review was to provide a critical assessment of all these aspects.

No longer failing to treat heart failure: A guideline update review.

Heart failure is a leading cause of hospital admissions and death in the United States and worldwide. In 2016, the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America released a joint focused guideline update for the management of patients with Stage C heart failure with reduced ejection fraction. An additional update released in 2017 reinforces the 2016 update's strong recommendation for substituting angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with an angiotensin receptor-neprilysin inhibitor to reduce morbidity and mortality in selected patients. The 2017 and 2016 updates also support adding a sinoatrial node modulator to further reduce heart rates in patients already maximized on beta-blocker therapy. These innovative therapies can significantly improve patients' quality of life and reduce the healthcare costs associated with managing heart failure.

Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure.

BACKGROUND: The US Food and Drug Administration approved the use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction in July 2015. We aimed to assess the adoption and prescription drug costs of sacubitril/valsartan in its first 18 months after Food and Drug Administration approval. METHODS AND RESULTS: Using a large US insurance database, we identified privately insured and Medicare Advantage beneficiaries who filled a first prescription for sacubitril/valsartan between July 1, 2015, and December 31, 2016. We compared them to patients treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Outcomes included adoption, prescription drug costs, and 180-day adherence, defined as a proportion of days covered ≥80%. A total of 2244 patients initiated sacubitril/valsartan. Although the number of users increased over time, the proportion of heart failure with reduced ejection fraction patients taking sacubitril/valsartan remained low (<3%). Patients prescribed sacubitril/valsartan were younger, more often male, with less comorbidity than those taking an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. Although a majority of prescription costs were covered by the health plan (mean, $328.37; median, $362.44 per 30-day prescription), out-of-pocket costs were still high (mean, $71.16; median, $40.27). By comparison, median out-of-pocket costs were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone. Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill patterns suggested that nearly half of nonadherent patients discontinued sacubitril/valsartan within 180 days of starting. CONCLUSIONS: Adoption of sacubitril/valsartan after Food and Drug Administration approval has been slow and may be associated with the high cost.

The Combination of Valsartan and Sacubitril in the Treatment of Hypertension and Heart Failure - an Update.

A novel antihypertensive drug, LCZ696 (Entresto®), has recently been introduced, which combines the action of an antagonist of the renin-angiotensin-aldosterone system (RAAS), effectively decreasing the blood pressure, with an inhibition of neprilysin, which is responsible for metabolizing natriuretic peptides exerting antihypertensive and antifibrotic effects. In this MiniReview, we describe the pharmacokinetics and pharmacodynamics, efficacy and side effects of the combined angiotensin receptor antagonist and neprilysin inhibitor LCZ696. We summarize the effect of LCZ696 treatment of patients suffering from hypertension and heart failure (HF) and further highlight the role of this new drug as a treatment option in the future. In the earlier stages of the treatment of patients with heart failure, LCZ696 was superior in lowering the blood pressure compared to olmesartan, while the effect on blood pressure at long-term treatment was comparable for the two drugs. The numbers of adverse effects were comparable. LCZ696 was superior to enalapril in reducing mortality, hospitalizations and HF symptoms. Adverse effects were reduced with a slower up-titrating regimen of 6 weeks. The current results are promising and suggest that LCZ696 will be a new candidate for first-line treatment of HF. However, it needs to be explored whether LCZ696 is safe in pregnant women, what are the effects of long-term LCZ696 treatment on survival and whether the antifibrotic effects can be of major benefit in, for example HF with preserved ejection fraction.

Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines.

OBJECTIVES: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained. METHODS: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis. RESULTS: The incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647. CONCLUSIONS: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios.

Heart Failure Therapy in 2016: SHIFTing the PARADIGM From Antiquated Therapies Toward Novel Agents.

Heart failure (HF) continues to afflict millions of Americans, resulting in substantial clinical and economic burden to our society. Recent literature has highlighted the role of 2 novel therapies (an angiotensin receptor blocker/neprilysin inhibitor and ivabradine) in further reducing residual disease in HF. Simultaneously, evidence has mounted suggesting that older therapies like digoxin are not effective in contemporary practice and, in fact, may be harmful. This editorial summarizes the most recently published articles pertaining to both new and old HF therapies and provides a call to action to pharmacists on how to shift patients toward effective drug regimens.

Neprilysin Inhibitors: Emerging Therapy for Heart Failure.

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

Assessment of Drug-Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects.

BACKGROUND AND OBJECTIVE: LCZ696 (sacubitril/valsartan), a novel angiotensin receptor neprilysin inhibitor has been recently approved for the treatment of patients with heart failure (HF) and reduced ejection fraction. As several HF patients are likely to use statins as co-medications, the potential for a pharmacokinetic drug-drug interaction between atorvastatin and LCZ696 was evaluated. METHODS: This was an open-label, three-period, single-sequence study in 28 healthy Chinese male subjects wherein LCZ696 200 mg was administered twice daily for 5 days in period 1. Following a washout period, atorvastatin 80 mg was administered once daily for 4 days (period 2) and subsequently co-administered with LCZ696 200 mg for 5 days (period 3). Serial plasma samples were collected to determine pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan) and atorvastatin and its metabolites. RESULTS: Atorvastatin co-administration had no effect on the pharmacokinetics of LBQ657, while the AUCτ,ss and C max,ss of sacubitril increased by 30 and 19 %, respectively, and the corresponding values for valsartan decreased by 19 and 9 %, respectively. Co-administration with LCZ696 increased C max,ss of atorvastatin, o-hydroxyatorvastatin, and p-hydroxyatorvastatin by 74, 68, and 108 %, respectively, and the AUCτ,ss of corresponding analytes increased by 34, 22, and 26 %, respectively. CONCLUSIONS: While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the C max of atorvastatin and its metabolites increased twofold, with a marginal increase in AUC (<1.3-fold). Multiple-dose administration of LCZ696 200 mg twice daily and atorvastatin 80 mg once daily either alone or in combination was generally safe and well tolerated in healthy subjects.

Cost-Effectiveness of Sacubitril-Valsartan Combination Therapy Compared With Enalapril for the Treatment of Heart Failure With Reduced Ejection Fraction.

OBJECTIVES: The objective of this study was to determine the cost-effectiveness and cost per quality-adjusted life year (QALY) gained of sacubitril-valsartan relative to enalapril for treatment of heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Compared with enalapril, combination angiotensin receptor-neprilysin inhibition (ARNI), as is found in sacubitril-valsartan, reduces cardiovascular death and heart failure hospitalization rates in patients with HFrEF. METHODS: Using a Markov model, costs, effects, and cost-effectiveness were estimated for sacubitril-valsartan and enalapril therapies for the treatment of HFrEF. Patients were 60 years of age at model entry and were modeled over a lifetime (40 years) from a third-party payer perspective. Clinical probabilities were derived predominantly from PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). All costs and effects were discounted at a 3% rate annually and are presented in 2015 U.S. dollars. RESULTS: In the base case, sacubitril-valsartan, compared with enalapril, was more costly ($60,391 vs. $21,758) and more effective (6.49 vs. 5.74 QALYs) over a lifetime. The cost-effectiveness of sacubitril-valsartan was highly dependent on duration of treatment, ranging from $249,411 per QALY at 3 years to $50,959 per QALY gained over a lifetime. CONCLUSIONS: Sacubitril-valsartan may be a cost-effective treatment option depending on the willingness-to-pay threshold. Future investigations should incorporate real-world evidence with sacubitril-valsartan to further inform decision making.