Dementia‐related adverse events in <scp>PARADIGM‐HF</scp> and other trials in heart failure with reduced ejection fraction

Cannon, Jane A.; Shen, Li; Jhund, Pardeep S.; Kristensen, Søren Lund; Køber, Lars; Chen, Fabian; Gong, Jianjian; Lefkowitz, Martin; Rouleau, Jean L.; Shi, Victor; Swedberg, Karl; Zile, Michael R.; Solomon, Scott D.; Packer, Milton; McMurray, John J.V.; Committees,

doi:10.1002/ejhf.687

Cited by 99 publications

(59 citation statements)

References 25 publications

(33 reference statements)

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“…In narrow term analysis, 12 cases were identified with sacubitril/valsartan compared to 15 with enalapril (HR 0.73, 95% CI: 0.33–1.59). Following age adjustment, the rates of dementia‐related adverse events were similar in both treatment arms to the three other HFrEF trials . This analysis is limited based on adverse event reporting, and long‐term follow‐up may provide additional insights not reported in the 4.3‐year follow‐up of the PARADIGM‐HF trial.…”

Section: Tolerabilitymentioning

confidence: 84%

“…In response to the concern for potential amyloid-b peptide accumulation in the brain resulting from neprilsyn inhibition and the association of these peptides with the development of Alzheimer disease, a post hoc analysis was conducted to further investigate the incidence of dementia-related adverse events. 43 The authors analyzed PARADIGM-HF utilizing Standardized MedDRA Queries (SMQ) with "broad" and "narrow" preferred terms related to dementia-like adverse events. Examples of broad terms included "confusional state, somnolence, and delirium," while examples of narrow terms included "Alzheimer's type dementia, senile dementia."…”

Section: Tolerabilitymentioning

confidence: 99%

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PARADIGM‐HF Trial: Secondary Analyses Address Unanswered Questions

et al. 2018

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Our aim was to summarize published secondary analyses of the PARADIGM-HF trial. In the original trial, published in September 2014, sacubitril/valsartan significantly reduced the primary composite outcome of cardiovascular death or heart failure hospitalization compared to enalapril. This summary provides a resource for clinicians to review subsequent analyses of the landmark trial evaluating the benefit of sacubitril/valsartan in various subgroups and providing information regarding optimal use of this new therapy in the broader heart failure population. A full list of publications of the existing PARDADIGM-HF post hoc analyses was obtained and summarized, grouped by focus (e.g., severity of illness, tolerability). Twenty-six publications and one abstract analyzing the PARADIGM-HF trial were reviewed, summarizing the most important results that compared the benefits of sacubitril/valsartan to enalapril, including pertinent subgroup information from each analysis. Key publications evaluated the treatment effect of sacubitril/valsartan based on heart failure severity (i.e., ejection fraction or heart failure risk scores), impact on alternate outcomes, influence of additional therapies, tolerability in patients with comorbidities (i.e., diabetes), long-term benefits, and cost-effectiveness. In addition, nine ongoing phase III and phase IV clinical trials with sacubitril/valsartan were briefly summarized to address potential future uses in more extensive heart failure settings. The benefit of sacubitril/valsartan over enalapril for the primary endpoint in the PARADIGM-HF trial is maintained throughout numerous secondary analyses. Though the subgroups analyzed are based on participants from a single clinical trial, clinicians can more confidently incorporate this novel therapy into practice with expanded knowledge of these existing analyses as well as ongoing prospective trials.

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Section: Tolerabilitymentioning

confidence: 84%

Section: Tolerabilitymentioning

confidence: 99%

PARADIGM‐HF Trial: Secondary Analyses Address Unanswered Questions

et al. 2018

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“…One area of particular concern is any effect of Entresto ® to contribute to Alzheimer disease (AD), as animal models demonstrate a role of neprilysin to degrade pathogenic amyloid-β [209]. Current clinical assessments of changes in pathogenic amyloid-β [210] or dementia-related events [211] with Entresto ® have not revealed a safety concern; however, longer follow-up studies are still warranted to exclude such concerns.…”

Section: 0 Angiotensin Receptor Neprilysin Inhibitor (Arni)mentioning

confidence: 99%

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

Ferrario

Mullick

2017

Pharmacological Research

101

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A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1-7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase –the primary angiotensin II forming enzyme in the human heart–, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.

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“…There was no increase in the risk of dementia or cognitive decline over the median follow-up time of 27 months in the patients treated with sacubitril/valsartan in PARADIGM-HF 44. In young cynomolgus monkeys, sacubitril/valsartan resulted in increased amyloid-β in the cerebrospinal fluid (CSF) but there were no amyloid plaques in the brain parenchyma 23.…”

Section: Effects Of Sacubitril/valsartan On Amyloid-βmentioning

confidence: 99%

Sacubitril/valsartan: beyond natriuretic peptides

Singh

Burrell

Cherif

et al. 2017

Heart

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Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to potentially beneficial physiological effects.The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Secondly, this review explores other hormones that are augmented by sacubitril/valsartan such as, bradykinin, substance-P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid β homeostasis with potential implications on Alzheimer's disease and macular degeneration. Finally, we explore the concept of 'auto-inhibition' which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that auto-inhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.

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Dementia‐related adverse events in PARADIGM‐HF and other trials in heart failure with reduced ejection fraction

Cited by 99 publications

References 25 publications

PARADIGM‐HF Trial: Secondary Analyses Address Unanswered Questions

PARADIGM‐HF Trial: Secondary Analyses Address Unanswered Questions

Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease

Sacubitril/valsartan: beyond natriuretic peptides

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