Evidence map›Other cardiovascular drugs × cardiovascular events›PMID 25176136›Full record

Trial reportThe New England journal of medicine2014

Ivabradine in stable coronary artery disease without clinical heart failure.

Kim Fox, Ian Ford, Philippe Gabriel Steg, Jean-Claude Tardif, Michal Tendera, Roberto Ferrari, SIGNIFY Investigators

3 registry-linked trialsOpen access · bronzeAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Publisher
In one paragraph

Trial report in The New England journal of medicine, 2014. The graph read 1 number from its abstract, feeding 1 cell of the map: it finds no clear difference in 1. It is linked to 3 registered trials, which are not on this map. Cited by 156 papers, 9 of them syntheses that pooled it.

1number the graph read from it
1cell of the map it votes in
156citing papers in PubMed, 9 pooled it
45.2field-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.

← favours the treatmentfavours the comparator →
1 · no effect
Cardiovascular eventsno clear difference · against placebo · ascvd, heart_failurefeeds one cell of the map
HR 1.080.96 to 1.20P=0.20
After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P=0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction.
FeedsOther cardiovascular drugs×cardiovascular events

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

Other cardiovascular drugs×cardiovascular events

InconclusiveOpen on the map →What to test next →

2 readable studies in this cell: 1 favour the treatment, 1 find no difference, 0 favour the comparator.

Belief with this paper
0.25no deciding trial · 0 families support, 0 contradict · against placebo
Without itThis paper is the only evidence family behind the claim. Without it there is no number.
← favours the treatmentfavours the comparator →
1 · no effect
This paper · 2014
HR 1.080.96 to 1.20
Canagliflozin and iron metabolism in the CREDENCE trial.PMID 39304530 · 2025
HR 0.700.56 to 0.87
4 · 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.

NCT02446990 phase3completednot on this map

Effects of Ivabradine in Patients With Stable Coronary Artery Disease Without Clinical Heart Failure. A Randomised Double-blind Placebo-controlled International Multicenter Study. Study Assessing the Morbi-mortality Benefits of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease

TypeinterventionalSponsorInstitut de Recherches Internationales ServierRan2009 to 2014Enrolled19,102ConditionsCoronary Artery DiseaseArmsIvabradine, Placebo
NCT02584439 phase3completednot on this mapstarted 2015, after this paper: background citation

Effect of Pharmacological Heart Rate Reduction on Visco-elastic Properties of the Arterial Wall (BRADYVASC)

TypeinterventionalSponsorUniversity Hospital, RouenRan2015 to 2019Enrolled20ConditionsHealthy, Vascular Stiffness, AgingArmsivabradine, lactose capsule (placebo)
NCT05261464 phase4unknown statusnot on this mapstarted 2021, after this paper: background citation

Heart Rate Controller in Computed Tomography Coronary Angiography: A Randomized Controlled Trial of Metoprolol, Diltiazem and Ivabradine

TypeinterventionalSponsorMahidol UniversityRan2021 to 2022Enrolled246ConditionsHeart Rate, Coronary Computed Tomography AngiographyArmsMetoprolol tartrate, Ivabradine, Diltiazem
5 · Its place in the literature

Who cites it

156 citing papers in PubMed, 9 syntheses or guidelines pooled it, 479 citations in OpenAlex.

  1. Pooled it
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  9. Resting heart rate and all-cause and cardiovascular mortality in the general population: a meta-analysis.CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne · 2016
    Pooled it
  10. Trial
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  17. Resting heart rate, heart rate variability and functional decline in old age.CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne · 2015
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96 more citing papers are in PubMed but not listed here.

6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

7 authors at 6 institutions in 6 countries.

Kim FoxFrom the National Heart and Lung Institute, Imperial College, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, London (K.F., P.G.S.), and the Robertson Centre for Biostatistics, University of Glasgow, Glasgow (I.F.) - both in the United Kingdom; Département Hospitalo-Universitaire Fibrosis Inflammation Remodeling, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, INSERM Unité 1148, and Université Paris-Diderot, Sorbonne Paris Cité - all in Paris (P.G.S.); the Montreal Heart Institute Coordinating Centre, Université de Montréal, Montreal (J.-C.T.); the Third Division of Cardiology, Medical University of Silesia, Katowice, Poland (M.T.); and the Department of Cardiology and Laboratory for Technologies of Advanced Therapies Center, University Hospital of Ferrara and Maria Cecilia Hospital, GVM Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy (R.F.).
Ian Ford
Philippe Gabriel Steg
Jean-Claude Tardif
Michal Tendera
Roberto Ferrari
SIGNIFY Investigators
Lung Institute · USMaria Cecilia Hospital · ITMedical University of Silesia · PLMontreal Heart Institute · CAUniversité Paris Cité · FRUniversity of Glasgow · GB

Funding

No grant is acknowledged in the PubMed record.

8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

backgroundAn elevated heart rate is an established marker of cardiovascular risk. Previous analyses have suggested that ivabradine, a heart-rate-reducing agent, may improve outcomes in patients with stable coronary artery disease, left ventricular dysfunction, and a heart rate of 70 beats per minute or more.

methodsWe conducted a randomized, double-blind, placebo-controlled trial of ivabradine, added to standard background therapy, in 19,102 patients who had both stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more (including 12,049 patients with activity-limiting angina [class ≥II on the Canadian Cardiovascular Society scale, which ranges from I to IV, with higher classes indicating greater limitations on physical activity owing to angina]). We randomly assigned patients to placebo or ivabradine, at a dose of up to 10 mg twice daily, with the dose adjusted to achieve a target heart rate of 55 to 60 beats per minute. The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction.

resultsAt 3 months, the mean (±SD) heart rate of the patients was 60.7±9.0 beats per minute in the ivabradine group versus 70.6±10.1 beats per minute in the placebo group. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P=0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P=0.02 for interaction). The incidence of bradycardia was higher with ivabradine than with placebo (18.0% vs. 2.3%, P<0.001).

conclusionsAmong patients who had stable coronary artery disease without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes. (Funded by Servier; SIGNIFY Current Controlled Trials number, ISRCTN61576291.).

Indexed as

Adrenergic beta-AntagonistsAgedAngina, StableAngiotensin-Converting Enzyme InhibitorsBenzazepinesCardiovascular DiseasesCoronary Artery DiseaseDouble-Blind MethodDrug Therapy, CombinationFemaleHeart FailureHeart RateHumansHydroxymethylglutaryl-CoA Reductase InhibitorsIntention to Treat AnalysisIvabradineAdrenergic beta-AntagonistsAngiotensin-Converting Enzyme InhibitorsBenzazepinesHydroxymethylglutaryl-CoA Reductase InhibitorsIvabradine

Identifiers

PMID25176136
OpenAlexW2153622558

What Socratic holds

Texttitle and abstract
Read underepoch 390

Registered trials

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.