Evidence map›Paper›PMID 27283779›Full record

Trial reportEuropean journal of heart failure2016

Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

Orly Vardeny, Brian Claggett, Milton Packer, Michael R Zile, Jean Rouleau, Karl Swedberg, John R Teerlink, Akshay S Desai, Martin Lefkowitz, Victor Shi and 3 more

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

Trial report in European journal of heart failure, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 7 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
111citing papers in PubMed, 7 pooled it
16.4field-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

111 citing papers in PubMed, 7 syntheses or guidelines pooled it, 225 citations in OpenAlex.

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  14. Clinical outcomes according to the average daily dose of sacubitril/valsartan: a nationwide longitudinal cohort study.Clinical research in cardiology : official journal of the German Cardiac Society · 2026
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51 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 10 institutions in 4 countries.

Orly VardenyPharmacy Practice Division, University of Wisconsin School of Pharmacy, Madison, WI, USA.
Brian ClaggettCardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
Milton PackerDivision of Cardiology; Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, USA.
Michael R ZileMedical University of South Carolina and Ralph H. Johnston Veterans Administration Medical Center, Charleston, NC, USA.
Jean RouleauInstitut de Cardiologie de Montreal, Université de Montréal, Montreal, Canada.
Karl SwedbergUniversity of Gothenburg, Gothenburg, Sweden and National Heart and Lung Institute, Imperial College, London, UK.
John R TeerlinkUniversity of California-San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
Akshay S DesaiCardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
Martin LefkowitzNovartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Victor ShiNovartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
John J V McMurrayBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Scott D SolomonCardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. ssolomon@rics.bwh.harvard.edu.
Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Investigators
Brigham and Women's Hospital · USBaylor University Medical Center · USBritish Heart Foundation · GBLung Institute · USMedical University of South Carolina · USMontreal Heart Institute · CANovartis (United States) · USTris Pharma (United States) · USUniversity of California, San Francisco · USUniversity of Wisconsin–Madison · US

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

aimsIn this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. METHODS AND

resultsIn a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001).

conclusionsIn PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs.

Indexed as

AgedAminobutyratesAngiotensin Receptor AntagonistsBiphenyl CompoundsDose-Response Relationship, DrugDouble-Blind MethodDrug CombinationsEnalaprilFemaleHeart FailureHumansMaleMiddle AgedStroke VolumeTetrazolesValsartanAminobutyratesAngiotensin Receptor AntagonistsBiphenyl CompoundsDrug CombinationsEnalaprilsacubitril and valsartan sodium hydrate drug combinationTetrazolesValsartanChronic heart failureClinical trialNeprilysin inhibitorSacubitrilValsartan

Identifiers

PMID27283779
PMCPMC5095784
OpenAlexW2413467082

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

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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 OpenQuestion graph.