Evidence map›Paper›PMID 27868321›Full record

Trial reportEuropean journal of heart failure2017

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

Jane A Cannon, Li Shen, Pardeep S Jhund, Søren L Kristensen, Lars Køber, Fabian Chen, Jianjian Gong, Martin P Lefkowitz, Jean L Rouleau, Victor C Shi and 6 more

Open access · hybridAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in European journal of heart failure, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed, 1 pooled it
11.4field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.

  1. Pooled it
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  6. The Impact of Cognitive Impairment on Cardiovascular Disease.Journal of the American College of Cardiology · 2025
    Review
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  10. Sacubitril/valsartan and the risk of incident dementia in heart failure: a nationwide propensity-matched cohort study.Clinical research in cardiology : official journal of the German Cardiac Society · 2024
    Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors at 9 institutions in 6 countries.

Jane A CannonBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Li ShenBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Pardeep S JhundBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Søren L KristensenRigshospitalet Copenhagen University Hospital, Copenhagen.
Lars KøberRigshospitalet Copenhagen University Hospital, Copenhagen.
Fabian ChenNovartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Jianjian GongNovartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Martin P LefkowitzNovartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Jean L RouleauInstitut de Cardiologie, Université de Montréal, Montréal, Canada.
Victor C ShiNovartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Karl SwedbergDepartment of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London.
Michael R ZileMedical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA.
Scott D SolomonCardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Milton PackerBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA.
John J V McMurrayBHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
PARADIGM-HF Investigators and Committees
Novartis (United States) · USUniversity of Glasgow · GBBaylor University Medical Center · USBrigham and Women's Hospital · USCopenhagen University Hospital · DKLung Institute · USMedical University of South Carolina · USRigshospitalet · DKUniversité de Montréal · CA

Funding

Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart FailureR01HL123478 · NHLBI · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI ZILE, MICHAEL R · 2015 to 2018
$1.5M
NHLBI NIH HHS R01 HL123478
6 · The paper itself

Abstract

aimsInhibition 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. METHODS AND

resultsIn 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.

conclusionWe 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.

Indexed as

AgedAminobutyratesAmnesiaAngiotensin-Converting Enzyme InhibitorsAngiotensin Receptor AntagonistsBiphenyl CompoundsConfusionDeliriumDementiaDisorders of Excessive SomnolenceDrug CombinationsEnalaprilFemaleHeart FailureHumansMaleAminobutyratesAngiotensin-Converting Enzyme InhibitorsAngiotensin Receptor AntagonistsBiphenyl CompoundsDrug CombinationsEnalaprilNeprilysinsacubitril and valsartan sodium hydrate drug combinationTetrazolesValsartanARNIDementiaHeart failureNeprilysin inhibition

Identifiers

PMID27868321
PMCPMC5248626
OpenAlexW2551090271

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.