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Recent advances in the treatment of chronic heart failure.
Buckley, LF, Shah, AM
F1000Research. 2019
Abstract
After more than a decade of relatively modest advancements, heart failure therapeutic development has accelerated, with the PARADIGM-HF trial and the SHIFT trial demonstrated significant reductions in cardiovascular death and heart failure hospitalization for sacubitril-valsartan and in heart failure hospitalization alone for ivabradine. Several heart failure therapies have since received or stand on the verge of market approval and promise substantive advances in the treatment of chronic heart failure. Some of these improve clinical outcomes, whereas others improve functional or patient-reported outcomes. In light of these rapid advances in the care of adults living with chronic heart failure, in this review we seek to update the general practitioner on novel heart failure therapies. Specifically, we will review recent data on the implementation of sacubitril-valsartan, treatment of functional mitral regurgitation, sodium-glucose co-transporter-2 (SGLT-2) inhibitor therapy, agents for transthyretin amyloid cardiomyopathy, treatment of iron deficiency in heart failure, and the use of biomarkers or remote hemodynamic monitoring to guide heart failure therapy.
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2.
Sacubitril/Valsartan: Updates and Clinical Evidence for a Disease-Modifying Approach.
Fabris, E, Merlo, M, Rapezzi, C, Ferrari, R, Metra, M, Frigerio, M, Sinagra, G
Drugs. 2019;(14):1543-1556
Abstract
New therapeutic strategies aimed to tackle the rising socio-economic burden of heart failure (HF) have become an impelling priority. The new pharmacological class of angiotensin (Ang) receptor-neprilysin inhibitors (ARNI) prompted a real conceptual change in the treatment of HF moving from only the inhibition of the renin-Ang-aldosterone system and sympathetic nervous system to a strategy based on the concomitant pharmacological enhancement of endogenous natriuretic peptides. Sacubitril/valsartan, a first-in-class ARNI, has reduced the primary composite endpoint of cardiovascular death or HF hospitalisation, sudden cardiac death, disease progression and improved quality of life, compared with enalapril, in patients on evidence-based contemporary medical therapy. Our review underlines the increasing body of evidence supporting the efficacy of sacubitril/valsartan, which may be considered a new disease-modifying therapy and, after about 30 years of research, a real step forward in HF pharmacological therapy.
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3.
Sacubitril/valsartan: A practical guide.
Fonseca, C, Brito, D, Ferreira, J, Franco, F, Morais, J, Silva Cardoso, J, ,
Revista portuguesa de cardiologia. 2019;(5):309-313
Abstract
Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone. The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease. As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines. This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology.
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4.
The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond.
Kario, K
Current cardiology reports. 2018;(1):5
Abstract
PURPOSE OF REVIEW Sacubitril/valsartan (LCZ696) is a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of neprilysin and the angiotensin (AT1) receptor. A recent clinical trial PRARDIGM-HF demonstrated that this drug is superior to angiotensin-converting enzyme (ACE) inhibitors for improving the prognosis in the patients with heart failure, and this has resulted in the drug being included in clinical practice guidelines for the management of heart failure with reduced ejection fraction (EF). In addition, sacubitril/valsartan has been developed for the management of hypertension, because it has unique anti-aging properties. However, the clinical evidence of mechanism has not been well validated. RECENT FINDINGS A recent mechanistic study PARAMETER demonstrated that sacubitril/valsartan (LCZ696) is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Considering these results, sacubitril/valsartan may be an attractive therapeutic agent to treat the elderly with age-related hypertension phenotypes, such as drug-uncontrolled (resistant) hypertension characterized as systolic (central) hypertension (structural hypertension) and/or nocturnal hypertension (salt-sensitive hypertension). These are the high-risk hypertension phenotypes which are prone to develop heart failure with preserved EF and chronic kidney disease. Sacubitril/valsartan may be effective to suppress the age-related continuum from hypertension to heart failure, and it could be clinically useful not only for secondary prevention, but also as primary prevention of heart failure in uncontrolled elderly hypertensive patients.
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5.
Sacubitril/valsartan: A novel angiotensin receptor-neprilysin inhibitor.
Dargad, RR, Prajapati, MR, Dargad, RR, Parekh, JD
Indian heart journal. 2018;(Suppl 1):S102-S110
Abstract
OBJECTIVE To describe the efficacy, superiority and safety profile of the first-in-class angiotensin receptor-neprilysin inhibitor "Sacubitril/Valsartan" as compared to angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blocker (ARB) in heart failure (HF) patients, reviewing data available from both clinical and pre-clinical studies. Evidences on health care utilization outcomes such as hospitalizations and emergency department visits were also evaluated. MATERIAL (DATA SOURCE): Sources: Medical literature on 'Sacubitril/Valsartan' and 'Angiotensin Receptor-Neprilysin Inhibitor' was identified by searching databases (including, but not limited to, PubMed, Embase and HighWire) for articles published since 1991, bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the companies developing the drug. SEARCH STRATEGY We conducted separate searches for each of the interventions of interest. The timeframe for both searches spanned the period from January 1991 to the most recently published data available and focused on PubMed, Embase and HighWire indexed articles. The search strategies included a combination of indexing terms as well as free-text terms included separately in 'Keywords' section. To supplement the above searches and ensure optimal and complete literature retrieval, we performed a manual check of the references of recent relevant reviews and meta-analysis. Searches were last updated on 12th July 2017. SELECTION Studies in patients with hypertension who received sacubitril/valsartan combination drug were included. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well-controlled trials with appropriate statistical methodology was preferred. Relevant pharmacodynamics and pharmacokinetics data was also included. DATA EVALUATION Many clinical trials have been conducted comparing the efficacy of sacubitril/valsartan with other anti-hypertensives. The trials have shown sacubitril/valsartan to be more effective in improving symptoms and physical limitations, reducing the risk of cardiovascular (CV) death, HF hospitalization, and the overall mortality and morbidity compared to its counterparts. CONCLUSION Effective reduction of blood pressure to accepted goals is the key to reduce the risk of CV events and stroke. Dual inhibition of neprilysin and the angiotensin receptor with sacubitril/valsartan may represent an attractive and serendipitous therapeutic approach for a range of CV diseases, including hypertension and HF, in which vasoconstriction, volume overload and neuro-hormonal activation play a part in pathophysiology. Sacubitril/Valsartan appears to be more efficacious in reducing blood pressure than currently available ACEi and ARBs with a similar safety and tolerability profile. Besides, pleiotropic benefits like HbA1c reduction, better eGFR progression and a greater decrease in blood pressure and serum creatinine levels make this drug a novel addition to the current hypertension armamentarium.
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6.
Sacubitril/Valsartan: The Newest Neurohormonal Blocker for Guideline-Directed Medical Therapy for Heart Failure.
Baliga, RR
Heart failure clinics. 2018;(4):479-491
Abstract
The burden of heart failure is projected to increase over the next decade; it is predicted that 1 in every 33 Americans will be affected by heart failure. Given that heart failure currently results in more than 1 million hospitalizations every year and the estimated 5-year mortality is approximately 50%, therapies that will improve survival and the economic burden are urgently needed. It is anticipated that the cost of managing heart failure is going to be approximately $70 billion in 2030. Therefore, the recent addition of the combination of sacubitril/valsartan (LCZ696) to guideline-directed medical therapies should ameliorate this burden.
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7.
Sacubitril/Valsartan: potential treatment for paediatric heart failure.
Das, BB, Scholl, F, Vandale, B, Chrisant, M
Cardiology in the young. 2018;(9):1077-1081
Abstract
The Prospective comparison of angiotensin receptor antagonist Valsartan and neprilysin inhibitor Sacubitril with angiotensin-converting enzyme inhibitor (enalapril) to determine impact on Global Mortality and Morbidity in Heart Failure trial has demonstrated that Sacubitril/Valsartan is superior to Enalapril in reducing the risks of both sudden cardiac death and death from worsening heart failure. This novel combination, Sacubitril/Valsartan, is also shown to reduce the risk of hospitalisation and progression of heart failure in adults. However, the benefit of Sacubitril/Valsartan in paediatric heart failure patients is unknown. In this review, we discuss the similarities and differences in pathophysiology of heart failure in children versus adults, and the potential role of Sacubitril/Valsartan in paediatric heart failure patients.
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8.
Neprilysin Inhibitors in Cardiovascular Disease.
Kang, G, Banerjee, D
Current cardiology reports. 2017;(2):16
Abstract
Mortality from heart failure remains high despite advances in medical therapy over the last three decades. Angiotensin receptor-neprilysin inhibitor (ARNI) combinations are the latest addition to the heart failure medical armamentarium, which is built on the cornerstone regimen of beta blockers, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and aldosterone antagonists. Recent trial data have shown a significant mortality benefit from ARNIs, which, as of May 2016, have now received a class I recommendation for use in patients with heart failure and reduced ejection fraction from the major American and European cardiology societies.
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Integrating New Pharmacologic Agents into Heart Failure Care: Role of Heart Failure Practice Guidelines in Meeting This Challenge.
Adams, KF, Giblin, EM, Pearce, N, Patterson, JH
Pharmacotherapy. 2017;(6):645-656
Abstract
Heart failure is well recognized as a major public health concern not only due to severe and frequent adverse health outcomes but also related to the major financial burden this syndrome presents with advancing age in Western societies. Despite the dire need for more efficacious therapies and better application of existing advances, treatment gaps persist, and outcomes in heart failure remain poor, with continually high mortality and morbidity. Treatment guidelines provide one strategy for advancing quality of care in patients with heart failure. This approach, with well-known potential strengths and weaknesses, has both adherents and detractors. Heart failure treatment guidelines have been in sharp focus recently due to updates that address the United States Food and Drug Administration (FDA) approval in 2015 of two new pharmacologic therapies for heart failure with reduced ejection fraction: sacubitril-valsartan and ivabradine. Our commentary will revisit issues in guideline methodology and discuss these in the context of the updates addressing the FDA approval of new pharmacologic agents for heart failure with reduced ejection fraction.
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10.
Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor-Neprilysin Inhibitor.
Ayalasomayajula, S, Langenickel, T, Pal, P, Boggarapu, S, Sunkara, G
Clinical pharmacokinetics. 2017;(12):1461-1478
Abstract
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1.9-fold for sacubitrilat, and ~1.7-fold for valsartan in healthy subjects. Following multiple twice-daily administration, steady-state maximum plasma concentration was reached within 3 days, showing no accumulation for sacubitril and valsartan, while ~1.6-fold accumulation for sacubitrilat. Sacubitril is eliminated predominantly as sacubitrilat through the kidney; valsartan is eliminated mainly by biliary route. Drug-drug interactions of sacubitril/valsartan were evaluated with medications commonly used in patients with heart failure including furosemide, warfarin, digoxin, carvedilol, levonorgestrel/ethinyl estradiol combination, amlodipine, omeprazole, hydrochlorothiazide, intravenous nitrates, metformin, statins, and sildenafil. Co-administration with sacubitril/valsartan increased the maximum plasma concentration (~2.0-fold) and area under the plasma concentration-time curve (1.3-fold) of atorvastatin; however, it did not affect the pharmacokinetics of simvastatin. Age, sex, or ethnicity did not affect the pharmacokinetics of sacubitril/valsartan. In patients with heart failure vs. healthy subjects, area under the plasma concentration-time curves of sacubitril, sacubitrilat, and valsartan were higher by approximately 1.6-, 2.1-, and 2.3-fold, respectively. Renal impairment had no significant impact on sacubitril and valsartan area under the plasma concentration-time curves, while the area under the plasma concentration-time curve of sacubitrilat correlated with degree of renal function (1.3-, 2.3-, 2.9-, and 3.3-fold with mild, moderate, and severe renal impairment, and end-stage renal disease, respectively). Moderate hepatic impairment increased the area under the plasma concentration-time curves of valsartan and sacubitrilat ~2.1-fold.