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1.
N Engl J Med ; 381(17): 1609-1620, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31475794

RESUMO

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Doenças Cardiovasculares/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Neprilisina/antagonistas & inibidores , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Idoso , Aminobutiratos/efeitos adversos , Angioedema/induzido quimicamente , Antagonistas de Receptores de Angiotensina/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipotensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Fatores Sexuais , Método Simples-Cego , Volume Sistólico , Tetrazóis/efeitos adversos , Valsartana/efeitos adversos
2.
Rev Med Chil ; 147(3): 330-333, 2019 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-31344170

RESUMO

BACKGROUND: Pharmacological treatment improves survival in patients with heart failure with reduced ejection fraction. The use of sacubutril/valsartan and ivabradine has been recently approved and incorporated in the latest guidelines. AIM: To identify candidates eligible for these therapies among patients treated in a heart failure clinic, considering the inclusion criteria for the PARADIGM-HF and SHIFT trials. MATERIAL AND METHODS: Cross-sectional study on 158 patients aged 62 ± 11 years (67% male) with heart failure and reduced ejection fraction, with at least three months of follow-up and without decompensation. The percentage of patients complying for the inclusion criteria for the PARADIGM-HF y SHIFT trials was determined. RESULTS: In 37%, the etiology of heart failure was ischemic, 49% were in functional class I, their ejection fraction was 33 ± 11% and their median Pro-brain natriuretic peptide was 800 pg/mL. Ninety five percent were treated with vasodilators, 97% with beta-blockers and 82% with aldosterone antagonists. Using PARADIGM-HF and SHIFT criteria, 11 patients (7%) were eligible for sacubitril / valsartan and 21 patients (13.3%) for ivabradine. Among the main causes of non-eligibility for sacubitril / valsartan were being functional class I (48.7%) and not achieving a stable dose of enalapril ≥ 20 mg / day or losartan ≥ 100 mg / day (24.7%). In the case of ivabradine, apart from those in functional class I, the absence of sinus rhythm and a heart rate < 70 / min when receiving a maximal tolerated dose of beta-blockers, were present in 22%. CONCLUSIONS: A low percentage of our patients were eligible for these therapies. Among the causes that explain these results were clinical stability, a high percentage of patients in functional class I and being in a disease modifying treatment.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Ivabradina/administração & dosagem , Tetrazóis/administração & dosagem , Idoso , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes
3.
Biomed Pharmacother ; 113: 108730, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861411

RESUMO

Arthritis is a common chronic joint disorder, with general symptoms including stiffness and joint pain. ß-methylphenylalanine is a well-known non-proteogenic unnatural amino acid. This study analyzes the anti-arthritic activity of ß-methylphenylalanine in experimental rats. The experimental groups were as follows: group I, sham; group II, control; group III, 100 mg/kg of ß-methylphenylalanine; and group IV, 200 mg/kg of ß-methylphenylalanine. Lipid peroxidation, glutathione peroxidase (Gpx), reduced glutathione (GSH), superoxide dismutase (SOD), catalase, prostaglandin E2 (PGE2), matrix metalloproteinase-3 (MMP-3), ceruloplasmin, zinc, copper, mRNA, and protein expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were determined. Supplementation with ß-methylphenylalanine significantly reduced lipid peroxidation, copper, PGE2 and MMP-3 levels, whereas GSH, Gpx, catalase, SOD and zinc levels were increased. Supplementation with ß-methylphenylalanine significantly reduced NF-κB mRNA expression by 26% and 47.8% in groups III and IV, respectively (P < 0.045), while iNOS mRNA expression was reduced by 14.3 and 47.6% in groups III and IV, respectively. NF-κB and iNOS protein expression increased by 160% and 120% respectively, in the control rats compared to the sham rats. However, supplementation with ß-methylphenylalanine significantly reduced NF-κB protein expression by 27% and 50% in groups III and IV, respectively, while iNOS protein expression was reduced by 22.7% and 45.4% in groups III and IV, respectively. Taken together, our data show that supplementation of ß-methylphenylalanine was effective against arthritis in a rat model.


Assuntos
Aminobutiratos/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Aminobutiratos/administração & dosagem , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Catalase/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Zinco/metabolismo
4.
Ir J Med Sci ; 188(4): 1169-1174, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30796605

RESUMO

INTRODUCTION: Sacubitril-valsartan has been shown by the PARADIGM-HF trial to decrease hospital admissions and improve mortality in patients with heart failure with reduced ejection fraction. The PARADIGM trial had stringent exclusion criteria. It is not known how applicable these trial criteria are to real-life practice. In this study, we sought to determine the percentage of patients eligible for sacubitril-valsartan therapy in a level 3 hospital without a dedicated heart failure service. METHODS: All patients discharged from our service with a diagnosis of congestive cardiac using our hospital in-patient enquiry (HIPE) system underwent hierarchal analysis. In order to be deemed eligible for sacubitril-valsartan therapy, patients had to meet PARADIGM-HF inclusion criteria. RESULTS: Our 143 patients represented a more clinically unwell, elderly cohort than the PARADIGM trial study population. Only 24 patients (16.66%) had an ejection fraction of 40% or less. Our results indicate that only 4/143 patients in a real-world setting (2.79%) were eligible for sacubitril-valsartan therapy at the point of discharge as per the PARADIGM-HF study criteria. This is primarily due to the higher than expected percentage of patients in our cohort with an ejection fraction of over 40% (n = 120) and the low percentage of patients on therapeutic doses of ACEI/ARB (n = 15). CONCLUSIONS: Our study showed that a smaller than expected proportion of our patients in real-world practice are suitable for sacubitril-valsartan therapy at discharge. Most patients were in the HFPEF cohort which does not currently have evidence for treatment with sacubitril-valsartan. Low rates of prescribing of basic heart failure medicatons and the absence of dedicated heart failure services in a non-tertiary centre may explain the poor compliance observed. Improving guideline adherence and increasing awareness of evidence-based medication use at primary and secondary care levels would be of benefit to Irish heart failure patients.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Insuficiência Cardíaca/mortalidade , Hospitalização/estatística & dados numéricos , Humanos , Alta do Paciente , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento
5.
Eur J Heart Fail ; 21(3): 337-341, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30741494

RESUMO

AIMS: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: Overall, 8399 patients with New York Heart Association class II-IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post-randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on-treatment analysis. CONCLUSION: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.


Assuntos
Aminobutiratos , Enalapril , Furosemida , Insuficiência Cardíaca , Volume Sistólico , Tetrazóis , Idoso , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Enalapril/administração & dosagem , Enalapril/farmacocinética , Feminino , Furosemida/administração & dosagem , Furosemida/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pessoa de Meia-Idade , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética
6.
7.
Int J Cardiol ; 281: 158-165, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420146

RESUMO

Sacubitril/valsartan represents the first of a new class of drugs able to act as a neprilysin inhibitor and as an angiotensin receptor blocker. This double inhibition has the advantage of concomitantly blocking a pro-fibrotic/pro-hypertrophic mechanism (angiotensin receptor blocker component) while stimulating an anti-fibrotic/anti-hypertrophic mechanism (neprilysin inhibitor component). Furthermore, the novel drug has natriuretic and diuretic properties, better preserves renal function, provides better blood pressure control as compared to renin angiotensin system inhibitors, and improves ventricular-arterial coupling. Consequently, sacubitril/valsartan provides greater target organ protection than angiotensin receptor blocker therapy alone, including cardiac, vascular, and renal protection. Up to now, this drug does not have an indication in patients with heart failure with preserved ejection fraction (HFpEF). However, its complex mechanism of action and previous experimental and clinical data seem to suggest its possible success in HFpEF. In this review we highlight and discuss the rationale, clinical insights, and perspectives behind the use of sacubitril/valsartan in HFpEF, specifically referring to its possible efficacy in pathophysiologic mechanisms, such as myocardial hypertrophy, fibrosis, and ischemia, renal dysfunction, impaired ventricular-arterial coupling, which are all tightly related to elevated left ventricular end diastolic pressure, a common hallmark for this multifaceted syndrome.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/administração & dosagem , Animais , Insuficiência Cardíaca/fisiopatologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Volume Sistólico/fisiologia
8.
J Oncol Pharm Pract ; 25(5): 1231-1234, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29945530

RESUMO

BACKGROUND: Sacubitril/valsartan has been shown to significantly reduce cardiovascular mortality and hospitalizations due to heart failure in adult patients with reduced ejection fraction when compared to enalapril. To the best of our knowledge, the combination of sacubitril (neprilysin inhibitor) and valsartan (angiotensin receptor blocker) has not been evaluated in patients with chemotherapy-induced cardiomyopathy, as these patients were excluded from the recent pivotal trial, PARADIGM-HF. However, current guidelines for the evaluation and management of cardiovascular complications of cancer therapy, published by the Canadian Cardiovascular Society, direct clinicians to the Canadian Cardiovascular Society Heart Failure Guidelines for the management of cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction (e.g. >10% reduction from baseline or left ventricular ejection fraction <53%), which could include the use of sacubitril/valsartan. METHODS: Retrospective descriptive comparative case study of two patients treated with sacubitril/valsartan. RESULTS: We present data from two patients who experienced anthracycline-induced cardiomyopathy and were successfully managed with sacubitril/valsartan after suboptimal responses to traditional evidence-based heart failure therapies. Both patients demonstrated some recovery of function and normalization of N-terminal pro B-type natriuretic peptide levels. Sacubitril/valsartan was well tolerated with minimal side effects. To date, neither patient has required hospitalization or additional clinic interventions for heart failure. CONCLUSIONS: While further large scale studies are required to determine a comprehensive safety and efficacy profile, we report two cases of anthracycline-induced cardiomyopathy survivors managed with sacubitril/valsartan with minimal side effects and no hospitalizations.


Assuntos
Aminobutiratos/administração & dosagem , Antraciclinas/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Idoso , Cardiomiopatias/induzido quimicamente , Quimioterapia Combinada , Feminino , Humanos , Estudos Retrospectivos
9.
Anticancer Res ; 39(1): 201-206, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591459

RESUMO

BACKGROUND: Oral mucositis (OM) induced by cancer chemotherapy has a high incidence and serious symptoms, which often force chemotherapy to be stopped. GGsTop is a newly-discovered gamma-glutamyl transpeptidase (GGT) inhibitor. Previous research suggested that inhibition of GGT suppressed reactive oxygen species and induced the production of collagen and elastin. We hypothesized that GGsTop could safely treat OM. MATERIALS AND METHODS: A mouse model of OM was treated with GGsTop and ulcer area, weight, and white blood cell count were determined. The treatment effect was also evaluated by hematoxylin-eosin and collagen staining. RESULTS: The therapeutic effect of GGsTop was better than that of an existing drug and may be safely used in combination with chemotherapy. Furthermore, GGsTop promoted collagen production in oral mucosa. CONCLUSION: GGsTop treated OM quickly and safely. GGsTop is highly valuable for use as a treatment for OM.


Assuntos
Aminobutiratos/administração & dosagem , Fluoruracila/efeitos adversos , Organofosfonatos/administração & dosagem , Estomatite/tratamento farmacológico , gama-Glutamiltransferase/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Fluoruracila/administração & dosagem , Humanos , Camundongos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Estomatite/induzido quimicamente , Estomatite/genética , Estomatite/patologia , gama-Glutamiltransferase/genética
10.
Int J Cardiol ; 271: 169-173, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30093137

RESUMO

BACKGROUND: Sacubitril/valsartan is the newest neurohormonal agent approved for therapy in patients with heart failure with reduced ejection fraction (HFrEF). Little is known about its acute and incremental hemodynamic effects. We aimed to evaluate the change in hemodynamic profiles measured using an implanted monitoring device in HFrEF patients initiated on sacubitril/valsartan therapy. METHODS: We prospectively enrolled 13 subjects with HFrEF and pre-implanted CardioMEMS™ device on maximally tolerated guideline-directed medical therapy and no contraindications to sacubitril/valsartan therapy. Transmitted pulmonary artery diastolic pressures (PAdP) from CardioMEMS™ were averaged and compared for one week before and after initiation of sacubitril/valsartan, as well as after change in medication strength and finally at three months. RESULTS: Sacubitril/valsartan dose increase was tolerated in 7/13 subjects with drug discontinuation in one subject after a week due to renal dysfunction. There was a significant reduction in mean PAdP after sacubitril/valsartan initiation compared to standard therapy (20.8 vs 18.3 mm Hg, p = 0.020). No further PAdP reduction was noted after sacubitril/valsartan dose increase (19.7 vs 20 mm Hg, p = 0.673) and at 3-month follow-up compared to baseline (20.8 vs 19.2 mm Hg, p = 0.352). CONCLUSIONS: Sacubitril/valsartan causes an acute reduction mean pulmonary artery pressures after initiation. However, no incremental reduction in PAdP was noted after dose increase and short-term follow-up. The current study demonstrates the utility of CardioMems™ device to study the drug's impact on hemodynamic profile in both short- and long-term follow-up.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Tetrazóis/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Seguimentos , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Volume Sistólico/fisiologia , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia
11.
Eur J Clin Pharmacol ; 74(9): 1121-1130, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29974143

RESUMO

PURPOSE: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co-administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure. METHODS: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days. Two hours after the morning dose of sacubitril/valsartan or placebo on day 5, subjects received intravenous nitroglycerin infusion at increasing doses up to 40 µg/min or placebo. Serial measurements of blood pressure (BP), heart rate, biomarkers and sacubitril/valsartan pharmacokinetics were conducted. RESULTS: Administration of nitroglycerin alone led to a dose- and time-dependent decrease in supine systolic BP (SBP) and diastolic BP (DBP) which was similar when nitroglycerin was co-administered with sacubitril/valsartan. At the highest dose of nitroglycerin, the mean (95% CI) decrease from baseline of SBP/DBP was 19.54 (- 21.99, - 17.09)/12.38 (- 13.85, - 10.92) mmHg for nitroglycerin alone compared to 22.63 (- 25.06, - 20.21)/12.94 (- 14.38, - 11.49) mmHg when co-administered with sacubitril/valsartan. Co-administration of sacubitril/valsartan and nitroglycerin did not result in further plasma cGMP increase compared to sacubitril/valsartan alone. The co-administration of nitroglycerin and sacubitril/valsartan was safe and well tolerated and did not impact the pharmacokinetics of sacubitril/valsartan. CONCLUSIONS: The results from this study demonstrate no pharmacodynamic drug interaction between nitroglycerin and sacubitril/valsartan in healthy subjects, suggesting that no change of dose selection and escalation recommendations or clinical monitoring during nitroglycerin administration is required.


Assuntos
Aminobutiratos/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Nitroglicerina/administração & dosagem , Tetrazóis/administração & dosagem , Administração Oral , Adulto , Aminobutiratos/farmacocinética , Biomarcadores/sangue , Estudos Cross-Over , GMP Cíclico/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Cálculos da Dosagem de Medicamento , Interações de Medicamentos , Monitoramento de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Tetrazóis/farmacocinética
13.
Am J Cardiovasc Drugs ; 18(6): 473-482, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29850980

RESUMO

The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time. Until recently, mortality benefits have been provided to patients with HF only by therapies that target the RAAS and SNS, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and beta-blockers. Sacubitril/valsartan, the first-in-class angiotensin receptor/neprilysin inhibitor (ARNI), targets both the NPS and RAAS to further improve clinical outcomes. This review discusses the focused management of patients with HF with reduced ejection fraction (HFrEF) and suggests changes to current management paradigms. From this assessment, the evidence supports favoring sacubitril/valsartan over ACEIs or ARBs, and this therapy should be used in conjunction with beta-blockers to further decrease morbidity and mortality in patients with HFrEF.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/administração & dosagem , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Doença Crônica , Combinação de Medicamentos , Frequência Cardíaca , Humanos , Peptídeos Natriuréticos/metabolismo , Neprilisina/antagonistas & inibidores , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Valsartana/administração & dosagem , Valsartana/efeitos adversos
14.
Am Heart J ; 199: 130-136, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29754651

RESUMO

BACKGROUND: Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. METHODS: This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. CONCLUSIONS: Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183).


Assuntos
Aminobutiratos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Tetrazóis/administração & dosagem , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Neprilisina , Estudos Prospectivos , Precursores de Proteínas , Volume Sistólico/fisiologia , Fatores de Tempo , Resultado do Tratamento
15.
Int J Cardiol ; 264: 118-123, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29776559

RESUMO

BACKGROUND: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. METHODS: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg. The study design incorporated two wash-out periods (~36 h each) to minimize any potential risk of angioedema due to overlapping ACE and neprilysin inhibition. Suspected cases of angioedema were reported to, and blindly adjudicated by, an independent angioedema adjudication committee (AAC). RESULTS: Of the 10,513 patients entering the enalapril run-in, 9419 entered the sacubitril/valsartan run-in and 8432 received double-blind treatment. Overall, 148 suspected angioedema events occurring in 144 patients were reported to AAC, with one event reported during screening period. Of the remaining 147 events, 54 were confirmed as angioedema by AAC. A confirmed event was experienced by 15 (0.14%) and 10 (0.11%) patients, during the enalapril and sacubitril/valsartan run-ins, respectively, and by 10 (0.24%) and 19 (0.45%) patients in the corresponding randomized arms during the double-blind phase. The frequency of confirmed angioedema was higher in black patients. Most events were mild. Only five patients required hospitalization and none required mechanical airway support. CONCLUSION: The number of confirmed angioedema events in PARADIGM-HF was low and there was no-marked excess risk of angioedema with sacubitril/valsartan versus enalapril.


Assuntos
Aminobutiratos , Angioedema , Antialérgicos/administração & dosagem , Enalapril , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis , Aminobutiratos/administração & dosagem , Aminobutiratos/efeitos adversos , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Angioedema/terapia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Método Duplo-Cego , Enalapril/administração & dosagem , Enalapril/efeitos adversos , Feminino , Insuficiência Cardíaca/fisiopatologia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Volume Sistólico/efeitos dos fármacos , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Resultado do Tratamento
17.
Eur J Heart Fail ; 20(4): 760-768, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29431251

RESUMO

AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.


Assuntos
Aminobutiratos/administração & dosagem , Enalapril/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/fisiologia , Tetrazóis/administração & dosagem , Idoso , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Estudos Prospectivos , Recidiva , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
18.
ESC Heart Fail ; 5(3): 275-283, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29464879

RESUMO

BACKGROUND: Sacubitril/valsartan significantly reduced heart failure hospitalization and mortality in PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). However, real-world data from its use are lacking. METHODS AND RESULTS: We retrospectively assessed all baseline and follow-up data of consecutive heart failure patients with reduced ejection fraction receiving therapy with sacubitril/valsartan for Class I recommendation between December 2016 and July 2017. Baseline characteristics and dose titration of sacubitril/valsartan were compared between patients in clinical practice and in PARADIGM-HF. A total of 120 patients (81% male) were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. A total of 20.1% of patients received dose uptitration. Patients were treated with an equipotential dose of renin-angiotensin system blockers before and after uptitration of sacubitril/valsartan (57 ± 29% vs. 53 ± 29% of target dose indicated by European Society of Cardiology guidelines; P = 0.286). However, they received a lower dose of sacubitril/valsartan in comparison with those in the PARADIGM-HF (219 ± 12 vs. 375 ± 75 mg; P < 0.001). In comparison with the patients receiving sacubitril/valsartan in PARADIGM-HF, patients in clinical practice were older and had a higher serum creatinine, higher New York Heart Association functional classification, and lower left ventricular ejection fraction (all P-value <0.05). Even in comparison with patients who experienced dropout during the run-in phase of PARADIGM-HF, real-world patients exhibited baseline characteristics indicative of more disease severity. Patients were at high absolute baseline risk for adverse outcome as illustrated by the EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) risk score of 6 (inter-quartile range 3), in comparison with 5 (inter-quartile range 4) in PARADIGM-HF. After initiation of sacubitril/valsartan, New York Heart Association class significantly improved (P < 0.001), but systolic blood pressure dropped more than was reported in PARADIGM-HF (7.1 ± 8.0 vs. 3.2 ± 0.4 mmHg; P < 0.001). CONCLUSIONS: Patients in clinical practice exhibit baseline characteristics associated with more severe disease, which might lead to prescription of lower doses. Nevertheless, patients in clinical practice are at high risk of adverse outcome as illustrated by the EMPHASIS-HF risk score, underscoring the large potential for sacubitril/valsartan therapy to reduce the risk of heart failure hospitalization and all-cause mortality.


Assuntos
Aminobutiratos/administração & dosagem , Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/fisiologia , Tetrazóis/administração & dosagem , Função Ventricular Esquerda/fisiologia , Idoso , Antagonistas de Receptores de Angiotensina/administração & dosagem , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos
19.
ESC Heart Fail ; 5(3): 222-230, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29469206

RESUMO

AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. METHODS AND RESULTS: The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. CONCLUSIONS: In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients.


Assuntos
Aminobutiratos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Síndromes da Apneia do Sono/tratamento farmacológico , Volume Sistólico/fisiologia , Tetrazóis/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Neprilisina , Polissonografia , Estudos Prospectivos , Síndromes da Apneia do Sono/complicações , Fatores de Tempo , Resultado do Tratamento
20.
Postgrad Med ; 130(3): 308-316, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29446691

RESUMO

OBJECTIVES: This study aimed to provide early insights into sacubitril/valsartan (sac/val) prescription patterns and the demographic and clinical characteristics of patients prescribed sac/val in primary care and cardiology settings in Germany. METHODS: The study used electronic medical records from the German IMS® Disease Analyzer database. Patients with ≥1 prescription for sac/val during 1 January-31 December 2016 (n = 1643) were identified and followed up for ≤12 months from first prescription. Patients with ≥1 heart failure (HF) diagnosis during the study period, ≥1 additional HF diagnosis in the full history of the database, and ≥1 prescription for an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and a ß-blocker during the study period, without a prescription for sac/val (n = 25,264), were included as a reference cohort. Changes in clinical parameters in the 12 months before and after sac/val initiation were investigated and compared with those from the PARADIGM-HF study. RESULTS: The characteristics of patients prescribed sac/val more closely resembled those of patients enrolled in PARADIGM-HF (e.g. younger age, higher proportion of men than women, lower systolic blood pressure) than patients in the reference cohort. Most patients were initiated on the lowest dose of sac/val irrespective of clinical setting. Significant decreases (p < 0.001) in NT-proBNP and glycated haemoglobin levels were observed following sac/val initiation. CONCLUSIONS: Patients prescribed sac/val had similar baseline demographics and clinical characteristics to those from PARADIGM-HF, and most patients were initiated on the lowest dose. Changes in clinical parameters before and after initiation mirrored findings from the PARADIGM-HF study.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/administração & dosagem , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea , Índice de Massa Corporal , Comorbidade , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Alemanha , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Estudos Retrospectivos , Fatores Sexuais , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos
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