Angiotensin 2 Type 1 Receptor Blockade with Neprilysin Inhibition for Chronic Heart Failure: A New Paradigm? (original) (raw)
Related papers
Research Reports in Clinical Cardiology
This study analyzes the safety and efficacy of LCZ696 (valsartan/sacubitril), a combination of angiotensin II receptor blocker and neprilysin inhibitor (ARNI), in patients with heart failure and preserved ejection fraction (HFpEF). Patients and Methods: An observational pilot study was conducted using a prospective design. A sample of 50 HFpEF patients (27 females and 23 males) was included on LCZ696 (50 mg orally, twice daily), which was then titrated up to a maximum tolerated dose, and followed up in the outpatient clinic. Thirty-seven patients received LCZ696 during hospitalization for decompensated heart failure or before their discharge while same titration was followed for the remaining patients. Results: Patients were classified as New York Heart Association (NYHA) class III (64%), NYHA class IV (22%), and NYHA class II (14%). Diabetes mellitus was found in 74% of patients, while hypertension in 94%. Rapid clinical improvement was found with significant reduction in NYHA class down to NYHA class II (p=0.018). Patients had cleared off the fine basal crackles (specific for the interstitial pulmonary disease) secondary to heart failure (p<0.001) and improvement or disappearance of edema of the lower limbs (p<0.001). Heart rate response and jugular venous pressure and NT-pro-BNP were reduced significantly (p-value <0.001, 0.005, respectively). Echocardiographic criteria for diastolic LV dysfunction (primarily E/A ratio) improved (p=0.001). Serum sodium (NA) levels improved significantly (p=0.015), without worsening renal function or limiting hyperkalemia. Conclusion: LCZ696 (sacubitril/valsartan; ARNI) led to significant clinical improvements in patients with HFpEF. Further, a randomized study is needed to test whether it leads to positive outcomes for a larger sample.
Revista Portuguesa de Cardiologia, 2019
The PARADIGM-HF population may be very different from real-world heart failure patients'' Resposta à Carta ao Editor «A população do PARADIGM-HF pode ser muito diferente do mundo real dos doentes com insuficiência cardíaca» To the Editor: As highlighted by our analysis, 1 the epidemiological study in Lima 2 pertinently quoted by Walter Calderón, and another two large registries, 3,4 patients from randomized trials are frequently different from those found in our daily practice. However, the results of the PARADIGM-HF trial are changing and will continue to change the way we treat patients with heart failure and reduced ejection fraction. Recently, the TRANSITION trial demonstrated the safety of sacubitril/valsartan when initiated prior to discharge from hospitalization for heart failure, achieving similar titration rates (62% vs. 68%), 5 and PIONEER-HF showed that in-hospital initiation of sacubitril/valsartan further reduced NT-proBNP values (ratio of NT-proBNP at week 4 and 8 to baseline value: 0.53 vs. 0.75). 6 Concluding, different pieces of an intricate puzzle are coming together, contributing to the widespread adoption of neuromodulation in patients with heart failure and reduced ejection fraction.
Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond
Vascular Health and Risk Management, 2015
Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction.
Objective: To describe the efficacy, superiority and safety profile of the first-in-class angiotensin receptorneprilysin inhibitor "Sacubitril/Valsartan" 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. Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction.
ESC Heart Failure, 2019
Aims Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine. All three studies evaluated patients with HFrEF, and the recommendations for use of GDMT were similar. A left ventricular ejection fraction ≤40% was required for entry into ANTHEM-HF and PARADIGM-HF and ≤35% for SHIFT. NYHA 2 or 3 symptoms were required for entry into ANTHEM-HF, and patients with predominantly NYHA 2 or 3 symptoms were enrolled in PARADIGM-HF and SHIFT. Methods and results Data on BPT were obtained from peer-reviewed publications and the public domain. Pearson's χ 2 test was used to evaluate differences in proportions, and Student's unpaired t-test was used to evaluate differences in mean values. The minimum period of stable GDMT required before randomization was longer in ANTHEM-HF: 3 months vs. 1 month in PARADIGM-HF and SHIFT, respectively. When compared with PARADIGM-HF and SHIFT, more patients in ANTHEM-HF received beta-blockers (100% vs. 93% and 89%, P < 0.04 and P < 0.007) and mineralocorticoid receptor antagonists (75% vs. 55% and 61%, P < 0.002 and P < 0.03). More patients in PARADIGM-HF received an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker than in ANTHEM-HF or SHIFT (100% vs. 85%, P < 0.0001, and 100% vs. 91%, P < 0.001), which was related to PARADIGM's design. When beta-blocker doses in ANTHEM-HF and SHIFT were compared, significantly fewer patients in ANTHEM-HF received doses ≥100% of target (10% vs. 23%, P < 0.02), and fewer patients tended to receive doses ≥50% of target (17% vs. 26%, P = 0.11). When ANTHEM-HF and PARADIGM-HF were compared, more patients in ANTHEM-HF tended to receive doses ≥100% of target (10% vs. 7%, P = 0.36), and fewer patients tended to receive doses ≥50% of target (17% vs. 20%, P = 0.56). Conclusions Background treatment with GDMT in ANTHEM-HF compared favourably with that in two other contemporary trials of new HF therapies. The minimum period of stable GDMT required before randomization was longer, and GDMT remained unchanged for the study's duration. These findings serve to further support the potential role of autonomic regulation therapy as an adjunct to GDMT for patients with HFrEF.