RESUMO
The association of an angiotensin II receptor antagonist and a neprilysin inhibitor (ARNI or Angiotensin Receptor-Neprilysin Inhibitor) is a new actor in the management of heart failure with reduced left ventricular ejection fraction (LVEF). The PARADIGM-HF trial performed in outpatients with a LVEF ≤ 35-40â % demonstrated that sacubitril-valsartan was superior to enalapril in reducing cardiovascular mortality and heart failure hospitalizations. Precautions in the initiation of sacubitril-valsartan, its use as well as its place in the drug management strategy for chronic heart failure are described in the present review. Additional data in patients hospitalized with reduced LVEF, in patients with LVEF > 45â % as well as the effects on blood pressure, renal or cognitive functions are presented.
L'association d'un antagoniste des récepteurs de l'angiotensine II et d'un inhibiteur de la néprilysine (ARNIâ : Angiotensin Receptor-Neprilysin Inhibitor) est un acteur supplémentaire dans la prise en charge de l'insuffisance cardiaque à fraction d'éjection ventriculaire gauche (FEVG) diminuée. L'étude PARADIGM-HF, conduite chez des patients ambulatoires (FEVG ≤ 35-40â %), a montré que la combinaison sacubitril-valsartan était supérieure à l'énalapril en réduisant la mortalité cardiovasculaire et les hospitalisations pour insuffisance cardiaque. Les modalités d'introduction, certaines précautions d'emploi, ainsi que sa place dans la stratégie de prise en charge médicamenteuse, sont décrites. Les autres données chez les patients hospitalisés avec FEVG diminuée, les patients avec FEVG > 45â % ainsi que les effets sur la pression artérielle, la fonction rénale ou les troubles cognitifs sont abordés.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Cognição/efeitos dos fármacos , Combinação de Medicamentos , Enalapril/farmacologia , Enalapril/uso terapêutico , Insuficiência Cardíaca/metabolismo , Humanos , Rim/efeitos dos fármacos , Neprilisina/metabolismo , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Resultado do Tratamento , ValsartanaRESUMO
Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74-1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65-1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.
Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/administração & dosagem , Idoso , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Morte Súbita Cardíaca/etiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Enalapril/administração & dosagem , Enalapril/efeitos adversos , Feminino , Insuficiência Cardíaca/mortalidade , Hospitalização , Humanos , Hipotensão/induzido quimicamente , Hipotensão/mortalidade , Masculino , Neprilisina/antagonistas & inibidores , Volume Sistólico/fisiologia , Tetrazóis/efeitos adversos , Resultado do Tratamento , Valsartana/administração & dosagem , Valsartana/efeitos adversosRESUMO
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.
Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzazepinas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Humanos , Ivabradina , Guias de Prática Clínica como Assunto , Resultado do TratamentoRESUMO
The natriuretic peptide system (NPS) is intimately involved in cardiorenal homeostasis in health, and dysregulation of the NPS plays an important role in the pathophysiology of heart failure (HF). Indeed, the diuretic, vasorelaxation, beneficial remodeling, and potent neurohumoral inhibition of the NPS support the therapeutic development of chronic augmentation of the NPS in symptomatic HF. Further, chronic augmentation of the protective NPS and in early stages of HF may ultimately prevent the progression of HF and reduced subsequent morbidity and mortality. In the current manuscript, we review the rationale for as well as previous and current efforts aimed at chronic therapeutic augmentation of the NPS in HF.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Peptídeos Natriuréticos/fisiologia , Peptídeos Natriuréticos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Quimioterapia Combinada , Insuficiência Cardíaca/prevenção & controle , Humanos , Peptídeos Natriuréticos/deficiência , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/uso terapêuticoRESUMO
Chronic heart failure is one of the most common chronic diseases worldwide with increasing prevalence and incidence. Due to the high morbidity and mortality a standardized and evidence-based therapy is essential. The present article gives an overview of the innovations from 2014 based on the current guidelines of the European Society of Cardiology. First, improvements of established medication regimens regarding beta blockers, mineralocorticoid receptor antagonists and treatment options for heart rate reduction and disease management programs will be explained. Second, new pharmacological developments, such as the new substance class of angiotensin receptor blockers and neprilysin inhibitors (ARNI), will be presented. Finally, new insights into common comorbidities of chronic heart failure patients, such as atrial fibrillation and hyperkalemia will be discussed.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Cardiologia/normas , Cardiopatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Guias de Prática Clínica como Assunto , Cardiotônicos/administração & dosagem , Doença Crônica , Europa (Continente) , Medicina Baseada em Evidências , Alemanha , Cardiopatias/diagnóstico , Humanos , Neprilisina/antagonistas & inibidores , Resultado do TratamentoRESUMO
Management of all pathologies, and in particular that of the most frequent ones, should whenever possible be based on robust evidence and arguments. New studies published this year enable rationalizing of screening in certain clinical situations, more adequate treatment of others, and open the way for novel and apparently very effective treatments. Whether it be the screening of carotid stenosis, the treatment of pericarditis, of heart failure, of chronic obstructive lung disease or spontaneous bacterial peritonitis, paradigm changes are conceivable. This selective review of the literature summarizes certain studies published this year.
Assuntos
Medicina Interna/tendências , Antagonistas Adrenérgicos beta/efeitos adversos , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Doenças Assintomáticas , Fibrilação Atrial/complicações , Compostos de Bifenilo , Estenose das Carótidas/diagnóstico , Colchicina/uso terapêutico , Diuréticos/uso terapêutico , Combinação de Medicamentos , Insuficiência Cardíaca/tratamento farmacológico , Hospitais , Humanos , Cirrose Hepática/complicações , Entorpecentes/uso terapêutico , Neprilisina/antagonistas & inibidores , Pericardite/prevenção & controle , Peritonite/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/terapia , Terapia Respiratória , Espironolactona/uso terapêutico , Acidente Vascular Cerebral/etiologia , Tetrazóis/uso terapêutico , ValsartanaRESUMO
INTRODUCTION AND OBJECTIVES: Transcatheter edge-to-edge repair (TEER) should be considered in patients with heart failure and secondary mitral regurgitation (MR). Angiotensin receptor-neprilysin inhibitors (ARNIs) have been demonstrated to improve prognosis in heart failure. We aimed to evaluate the impact ARNIs on patient selection and outcomes. METHODS: The population of the Spanish TEER prospective registry (March 2012 to January 2021) was divided into 2 groups: a) TEER before the ARNI era (n=450) and b) TEER after the recommendation of ARNIs by European Guidelines (n=639), with further analysis according to intake (n=52) or not (n=587) of ARNIs. RESULTS: A total of 1089 consecutive patients underwent TEER for secondary MR. In the ARNI era, there was a reduction in left ventricle dilation (82mL vs 100mL, P=.025), and better function (35% vs 38%, P=.011). At 2 years of follow-up, mortality (10.6% vs 17.3%, P <.001) and heart failure readmissions (16.6% vs 27.8%, P <.001) were lower in the ARNI era, but not recurrent MR. In the ARNI era, 1- and 2-year mortality were similar irrespective of ARNI intake but patients on ARNIs had a lower risk of readmission+mortality at 2 years (OR, 0.369; 95%CI, 0.137-0.992; P=.048), better NYHA class, and lower recurrence of MR III-IV (1.9% vs 14.3%, P=.011). CONCLUSIONS: Better patient selection for TEER has been achieved in the last few years with a parallel improvement in outcomes. The use of ARNIs was associated with a significant reduction in overall events, better NYHA class, and lower MR recurrence.
Assuntos
Insuficiência Cardíaca , Insuficiência da Valva Mitral , Neprilisina , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/tratamento farmacológico , Insuficiência da Valva Mitral/cirurgia , Neprilisina/antagonistas & inibidores , Receptores de Angiotensina , Resultado do TratamentoRESUMO
INTRODUCTION: The European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines all currently recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) in the treatment of HF with a reduced ejection fraction (HFrEF). Newer medications targeting combining an ARB with a neprilysin inhibitor (ARNI) sacubitril/valsartan have shown benefits in mortality and can be used in place of an ACE inhibitor or an ARB. Additionally, dapagliflozin, a medication targeting the sodium-glucose cotransporter 2 (SGLT2) can be used in addition to current therapies. AREAS COVERED: This review provides a comprehensive analysis of the evidence around the new pharmacotherapies for HFrEF, specifically, sacubitril/valsartan and dapagliflozin. A comprehensive review of the literature using keywords such as heart failure with reduced ejection fraction, angiotensin receptor, neprilysin inhibitor, and sodium glucose transporter was conducted within the National Centre for Biotechnology Information (NCBI) and Google Scholar databases. The reference sections of articles were also examined to find additional articles. EXPERT OPINION: Sacubitril/valsartan and dapagliflozin both show marked benefits on mortality in HFrEF patients. More research needs to be conducted on the mechanisms of action on disease modification.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/tratamento farmacológico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Humanos , Neprilisina/antagonistas & inibidores , Volume Sistólico , Resultado do TratamentoRESUMO
Importance: In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan. Objective: To describe changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase. Interventions: Sacubitril/valsartan titrated to 97/103 mg twice daily. Design, Setting, and Participants: The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 and May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study. Main Outcomes and Measures: Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12. Results: Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined -17.2% (95% CI, -3.2 to -29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (-37.4%; 95% CI, -28.1 to -45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97). Conclusions and Relevance: Switching patients' treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF. Trial Registration: ClinicalTrials.gov identifier: NCT02554890.
Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/análise , Neprilisina/antagonistas & inibidores , Fragmentos de Peptídeos/análise , Tetrazóis/uso terapêutico , Doença Aguda , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo , Combinação de Medicamentos , Enalapril/uso terapêutico , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , ValsartanaRESUMO
AIM: This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. METHODS AND RESULTS: We enrolled 73 chronic HF patients who were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose-dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon-like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a â¼4-fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT-proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). CONCLUSION: Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.
Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Fator Natriurético Atrial/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/metabolismo , Neprilisina/metabolismo , Fragmentos de Peptídeos/metabolismo , Tetrazóis/uso terapêutico , Idoso , Compostos de Bifenilo , Antígeno CD146/metabolismo , Doença Crônica , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Ecocardiografia , Feminino , Frutosamina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Substância P/metabolismo , Resultado do Tratamento , Troponina I/metabolismo , ValsartanaRESUMO
Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP-1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Hipoglicemiantes/uso terapêutico , Neprilisina/antagonistas & inibidores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Neprilisina/metabolismoRESUMO
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.
Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/economia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Bifenilo , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/antagonistas & inibidores , Volume Sistólico/efeitos dos fármacos , Tetrazóis/economia , Resultado do Tratamento , Valsartana/economia , Disfunção Ventricular Esquerda/tratamento farmacológico , Adulto JovemRESUMO
INTRODUCTION: Heart failure remains a syndrome with a very high mortality rate and a poor quality of life. For patients with heart failure and a preserved ejection fraction (HFpEF), no drugs have shown to improve mortality and morbidity, and therefore novel drugs are highly needed. LCZ696 , a first in class angiotensin receptor neprilysin inhibitor (ARNi), might be an interesting novel drug for the treatment of heart failure. AREAS COVERED: Previous studies have shown promising effects of a combination drug with a neutral endopeptidase and an angiotensin-converting enzyme inhibitor (omapatrilat) for the treatment of patients with heart failure. However, the occurrence of angioedema prevented the drug from further development. The majority of this paper will discuss the metabolism, pharmacokinetics, pharmacodynamics, clinical effects, and safety of LCZ696, with a particular focus on heart failure. EXPERT OPINION: LCZ696 is superior to valsartan alone in reducing blood pressure. Preliminary results from a Phase II trial showed that LCZ696 reduced NT-proBNP to a greater extent than valsartan alone, and in addition LCZ696 had beneficial effects on symptoms. With these promising first results, the results of ongoing further studies in heart failure are eagerly awaited.
Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/administração & dosagem , Valina/análogos & derivados , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacocinética , Animais , Compostos de Bifenilo , Combinação de Medicamentos , Humanos , Neprilisina/antagonistas & inibidores , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Resultado do Tratamento , Valina/administração & dosagem , ValsartanaAssuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiomiopatia Hipertrófica/tratamento farmacológico , Segurança do Paciente , Aminobutiratos/farmacologia , Compostos de Bifenilo , Combinação de Medicamentos , Enalapril/farmacologia , Humanos , Neprilisina/antagonistas & inibidores , Tetrazóis/farmacologia , Resultado do Tratamento , Valsartana/farmacologiaRESUMO
Experimental and clinical studies over the past two decades have identified several interventions for slowing the progression of chronic renal disease towards end-stage renal failure. In this paper we review the experimental and clinical evidence in support of dietary protein restriction, angiotensin-converting enzyme inhibitor therapy, control of systemic hypertension, reduction of proteinuria, treatment of hyperlipidemia and smoking cessation. We also consider potential future renoprotective therapies. Finally we propose a comprehensive strategy for achieving maximal renoprotection with available interventions and monitoring.