Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.
ABSTRACT: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials.In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with 'broad' and 'narrow' preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF.We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.
Project description:The Prospective comparison of Angiotensin Receptor-neprilysin inhibitor (ARNI) with Angiotensin converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (HF) trial (PARADIGM-HF) showed that adding a neprilysin inhibitor (sacubitril) to a renin-angiotensin system blocker (and other standard therapy) reduced morbidity and mortality in ambulatory patients with chronic HF with reduced ejection fraction (HFrEF). In PARADIGM-HF, valsartan combined with sacubitril (a so-called ARNI) was superior to the current gold standard of an ACEI, specifically enalapril, reducing the risk of the primary composite outcome of cardiovascular (CV) death or first HF hospitalization by 20% and all-cause death by 16%. Following the results of PARADIGM-HF, sacubitril/valsartan was approved by American and European regulatory authorities for the treatment of HFrEF. The burden of HF in Asia is substantial, both due to the huge population of the region and as a result of increasing CV risk factors and disease. Both the prevalence and mortality associated with HF are high in Asia. In the following review, we discuss the development of sacubitril/valsartan, the prototype ARNI, and the available evidence for its efficacy and safety in Asian patients with HFrEF.
Project description:This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.
Project description:With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.
Project description:Angiotensin-converting enzyme inhibitors (ACEIs) have been the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF) for over two decades. Inhibition of neprilyisin augments vasoactive substances including natriuretic peptides, which may have multiple advantageous effects in chronic HF. Early studies of neprilyisin inhibition led to drug discontinuation due to lack of efficacy or safety concerns. Sacubitril/valsartan is a first-in-class combined angiotensin receptor/neprilysin inhibitor (ARNI). The PARADIGM-HF study demonstrated robust superiority of ARNI compared with enalapril in patients with chronic symptomatic HFrEF, raising the question of whether ACEI should still have a role in the management of HFrEF.
Project description: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). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. 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. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice.
Project description:Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35-40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor-neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin-angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin-angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.
Project description:Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk of morbidity and mortality. Sacubitril valsartan (previously known as LCZ696) is a new oral agent approved for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction. It is described as the first in class angiotensin receptor neprilysin inhibitor (ARNI) since it incorporates the neprilysin inhibitor, sacubitril and the angiotensin II receptor antagonist, valsartan. Neprilysin is an endopeptidase that breaks down several vasoactive peptides including natriuretic peptides (NPs), bradykinin, endothelin and angiotensin II (Ang-II). Therefore, a natural consequence of its inhibition is an increase of plasmatic levels of both, NPs and Ang-II (with opposite biological actions). So, a combined inhibition of these both systems (Sacubitril / valsartan) may enhance the benefits of NPs effects in HF (natriuresis, diuresis, etc) while Ang-II receptor is inhibited (reducing vasoconstriction and aldosterone release). In a large clinical trial (PARADIGM-HF with 8442 patients), this new agent was found to significantly reduce cardiovascular and all cause mortality as well as hospitalizations due to HF (compared to enalapril). This manuscript reviews clinical evidence for sacubitril valsartan, dosing and cautions, future directions and its considered place in the therapy of HF with reduced ejection fraction.
Project description:<h4>Objectives</h4>To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial.<h4>Methods</h4>A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ?40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization).<h4>Results</h4>The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05).<h4>Conclusion</h4>Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.
Project description:The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease.Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Neprilysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprilysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II-III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications.
Project description:<h4>Aims</h4>Sacubitril-valsartan has been shown to have superior effects over angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF) and hypertension. The efficacy and safety of sacubitril-valsartan in patients with HF are controversial. We performed a meta-analysis of randomized controlled trials to assess and compare the effect and adverse events of sacubitril-valsartan, valsartan, and enalapril in patients with HF.<h4>Methods and results</h4>We conducted a systematic search using PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. Randomized controlled trials involving the use of sacubitril-valsartan in patients with HF were included. We assessed the pooled odds ratio (OR) of all-cause mortality, cardiovascular mortality, and hospitalization for HF in fixed-effects models and the pooled risk ratio (RR) of symptomatic hypotension, worsening renal function, and hyperkalaemia in fixed-effects models. Of the 315 identified records, six studies involving 14 959 patients were eligible for inclusion. Sacubitril-valsartan reduced the endpoints of all-cause mortality and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF) in three trials with pooled ORs of 0.83 (P = 0.0006) and 0.78 (P < 0.0001), respectively. Regarding the composite outcome of hospitalization for HF in five trials, the pooled OR was 0.79 (P < 0.00001). Compared with enalapril or valsartan, sacubitril-valsartan was associated with a high risk of symptomatic hypotension (RR 1.47, P < 0.00001), low risk of worsening renal function (RR 0.81, P = 0.005), and low rate of serious hyperkalaemia (?6.0 mmol/L) (RR 0.76, P = 0.0007) in all six trials.<h4>Conclusions</h4>Compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, sacubitril-valsartan significantly decreased the risk of death from all causes or cardiovascular causes in HFrEF and hospitalization for HF in both patients with HFrEF and HF with preserved ejection fraction. Sacubitril-valsartan reduced the risk of renal dysfunction and serious hyperkalaemia but was associated with more symptomatic hypotension.