Evidence map›PCSK9 inhibitors × cardiovascular events›PMID 27777279›Full record

Trial reportCirculation2016

Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control.

Kausik K Ray, Henry N Ginsberg, Michael H Davidson, Robert Pordy, Laurence Bessac, Pascal Minini, Robert H Eckel, Christopher P Cannon

10 registry-linked trialsOpen access · greenAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Circulation, 2016. The graph read 2 numbers from its abstract, feeding 1 cell of the map: it . It is linked to 10 registered trials, which are not on this map. Cited by 49 papers, 1 of them a synthesis that pooled it.

2numbers the graph read from it
1cell of the map it votes in
49citing papers in PubMed, 1 pooled it
22.3field-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
MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization)alirocumab vs control (placebo/ezetimibe)favours the treatment · dyslipidemia, ascvdfeeds one cell of the map
HR 0.710.57 to 0.89P=0.003
Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003).
FeedsPCSK9 inhibitors×cardiovascular events
MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization)alirocumab vs control (placebo/ezetimibe)favours the treatment · dyslipidemia, ascvdfeeds one cell of the map
HR 0.760.63 to 0.91P=0.0025
For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025).
FeedsPCSK9 inhibitors×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.

PCSK9 inhibitors×cardiovascular events

No readable resultOpen on the map →What to test next →

10 readable studies in this cell: 8 favour the treatment, 2 find no difference, 0 favour the comparator.

Belief with this paper
1.00established · 6 families support, 0 contradict · against placebo
Without itNot a counted family in this claim, so removing it changes nothing.
← favours the treatmentfavours the comparator →
1 · no effect
This paper · 2016
HR 0.710.57 to 0.89
NCT0176463327,564 enrolled · 2013
HR 0.850.79 to 0.92
NCT0166340218,924 enrolled · 2012
HR 0.850.78 to 0.93
NCT0387240112,301 enrolled · 2019
HR 0.750.65 to 0.86
Cardiovascular event reduction with PCSK9 inhibition among 1578 patien…PMID 29685591
HR 0.830.44 to 1.54
Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab i…PMID 28927706 · 2017
HR 0.830.75 to 0.93
Efficacy and safety of alirocumab in reducing lipids and cardiovascula…PMID 25773378 · 2015
HR 0.520.31 to 0.90
Alirocumab after acute coronary syndrome in patients with a history of…PMID 34922353 · 2022
HR 0.850.78 to 0.93
Cardiovascular Outcomes and Efficacy of the PCSK9 Inhibitor Evolocumab…PMID 40544474 · 2025
HR 0.660.32 to 1.38
Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patient…PMID 28304242 · 2017
HR 0.790.65 to 0.97
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.

NCT01507831 phase3completednot on this map

Long-term Safety and Tolerability of SAR236553 (REGN727) in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid Modifying Therapy: A Randomized, Double-Blind, Placebo-Controlled Study

TypeinterventionalSponsorSanofiRan2012 to 2014Enrolled2,341ConditionsHypercholesterolemiaArmsPlacebo (for alirocumab), Alirocumab, Lipid-Modifying Therapy (LMT)
NCT01617655 phase3completednot on this map

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in Patients With Heterozygous Familial Hypercholesterolemia and LDL-C Higher or Equal to 160mg/dL With Their Lipid-Modifying Therapy

TypeinterventionalSponsorSanofiRan2012 to 2015Enrolled107ConditionsHypercholesterolaemiaArmsAlirocumab, Placebo (for alirocumab), Lipid Modifying Therapy (LMT)
NCT01623115 phase3completednot on this map

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

TypeinterventionalSponsorSanofiRan2012 to 2014Enrolled486ConditionsHypercholesterolemiaArmsAlirocumab, Placebo (for alirocumab), Lipid Modifying Therapy (LMT)
NCT01644175 phase3completednot on this map

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

TypeinterventionalSponsorSanofiRan2012 to 2014Enrolled316ConditionsHypercholesterolemiaArmsPlacebo (for alirocumab), Alirocumab, Lipid-Modifying Therapy (LMT)
NCT01644188 phase3completednot on this map

A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

TypeinterventionalSponsorSanofiRan2012 to 2015Enrolled720ConditionsHypercholesterolemiaArmsAlirocumab, Placebo (for alirocumab), Ezetimibe, Placebo (for ezetimibe), Lipid Modifying Therapy (LMT)
NCT01644474 phase3completednot on this map

A Randomized, Double-Blind, Active-Controlled, Parallel-Group Study to Evaluate the Efficacy And Safety of SAR236553/REGN727 Over 24 Weeks in Patients With Hypercholesterolemia

TypeinterventionalSponsorSanofiRan2012 to 2013Enrolled103ConditionsHypercholesterolemiaArmsAlirocumab, Ezetimibe, Placebo (for Alirocumab), Placebo (for Ezetimibe)
NCT01709500 phase3completednot on this map

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

TypeinterventionalSponsorRegeneron PharmaceuticalsRan2012 to 2015Enrolled249ConditionsHeterozygous Familial HypercholesterolemiaArmsLMT (atorvastatin, simvastatin, or rosuvastatin), alirocumab, Placebo
NCT01709513 phase3completednot on this map

A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Primary Hypercholesterolemia Who Are Intolerant to Statins

TypeinterventionalSponsorRegeneron PharmaceuticalsRan2012 to 2017Enrolled314ConditionsHypercholesterolemiaArmsAtorvastatin, Ezetimibe, Alirocumab, Placebo
NCT01730040 phase3completednot on this map

A Randomized, Double-Blind Study of the Efficacy and Safety of Alirocumab Added on to Atorvastatin Versus Ezetimibe Added on to Atorvastatin Versus Atorvastatin Dose Increase Versus Switch to Rosuvastatin in Patients Who Are Not Controlled on Atorvastatin

TypeinterventionalSponsorRegeneron PharmaceuticalsRan2012 to 2014Enrolled355ConditionsHypercholesterolemiaArmsAlirocumab, Atorvastatin, Ezetimibe, Rosuvastatin, Placebo
NCT01730053 phase3completednot on this map

A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added-on to Rosuvastatin Versus Ezetimibe Added-on to Rosuvastatin Versus Rosuvastatin Dose Increase in Patients Who Are Not Controlled on Rosuvastatin

TypeinterventionalSponsorRegeneron PharmaceuticalsRan2012 to 2014Enrolled305ConditionsHypercholesterolemiaArmsAlirocumab, Rosuvastatin, Ezetimibe, Placebo
5 · Its place in the literature

Who cites it

49 citing papers in PubMed, 1 synthesis or guideline pooled it, 128 citations in OpenAlex.

  1. Pooled it
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  9. Safety of the PCSK9 inhibitor alirocumab: insights from 47 296 patient-years of observation.European heart journal. Cardiovascular pharmacotherapy · 2024
    Review
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6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

8 authors at 5 institutions in 2 countries.

Kausik K RayFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.). k.ray@imperial.ac.uk.
Henry N GinsbergFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Michael H DavidsonFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Robert PordyFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Laurence BessacFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Pascal MininiFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Robert H EckelFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
Christopher P CannonFrom Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, London, UK (K.K.R.); Columbia University, New York, NY (H.N.G.); Department of Medicine, University of Chicago Medicine, Chicago, IL (M.H.D.); Regeneron Pharmaceuticals, Inc Tarrytown, NY (R.P.); Sanofi, Paris, France (L.B.); Biostatistics and Programming, Sanofi, Chilly-Mazarin, France (P.M.); University of Colorado, Anschutz Medical Campus, Aurora (R.H.E.); and Harvard Clinical Research Institute, Boston, MA (C.P.C.).
University of Colorado Anschutz Medical Campus · USColumbia University · USRegeneron (United States) · USSanofi (France) · FRUniversity of Chicago · US

Funding

PILOT STUDY--SUBSTRATE METABOLISM IN EXTREMELY LOW BIRTH WEIGHT INFANTSP30DK048520 · UNIVERSITY OF COLORADO DENVER · 1995 to 2025
$7.7M
8 · The paper itself

Abstract

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

backgroundA continuous relationship between reductions in low-density lipoprotein cholesterol (LDL-C) and major adverse cardiovascular events (MACE) has been observed in statin and ezetimibe outcomes trials down to achieved levels of 54 mg/dL. However, it is uncertain whether this relationship extends to LDL-C levels <50 mg/dL. We assessed the relationship between additional LDL-C, non-high-density lipoprotein cholesterol, and apolipoprotein B100 reductions and MACE among patients within the ODYSSEY trials that compared alirocumab with controls (placebo/ezetimibe), mainly as add-on therapy to maximally tolerated statin.

methodsData were pooled from 10 double-blind trials (6699 patient-years of follow-up). Randomization was to alirocumab 75/150 mg every 2 weeks or control for 24 to 104 weeks, added to background statin therapy in 8 trials. This analysis included 4974 patients (3182 taking alirocumab, 1174 taking placebo, 618 taking ezetimibe). In a post hoc analysis, the relationship between average on-treatment lipid levels and percent reductions in lipids from baseline were correlated with MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization) in multivariable analyses.

resultsOverall, 33.1% of the pooled cohort achieved average LDL-C <50 mg/dL (44.7%-52.6% allocated to alirocumab, 6.5% allocated to ezetimibe, and 0% allocated to placebo). In total, 104 patients experienced MACE (median time to event, 36 weeks). For every 39 mg/dL lower achieved LDL-C, the risk of MACE appeared to be 24% lower (adjusted hazard ratio, 0.76; 95% confidence interval, 0.63-0.91; P=0.0025). Percent reductions in LDL-C from baseline were inversely correlated with MACE rates (hazard ratio, 0.71; 95% confidence interval, 0.57-0.89 per additional 50% reduction from baseline; P=0.003). Strengths of association materially similar to those described for LDL-C were observed with achieved non-high-density lipoprotein cholesterol and apolipoprotein B100 levels or percentage reductions.

conclusionsIn a post hoc analysis from 10 ODYSSEY trials, greater percentage reductions in LDL-C and lower on-treatment LDL-C were associated with a lower incidence of MACE, including very low levels of LDL-C (<50 mg/dL). These findings require further validation in the ongoing prospective ODYSSEY OUTCOMES trial. CLINICAL

trial registrationURL: https://www.clinicaltrials.gov. Unique identifiers: NCT01507831, NCT01623115, NCT01709500, NCT01617655, NCT01644175, NCT01644188, NCT01644474, NCT01730040, NCT01730053, and NCT01709513.

Indexed as

AgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAnticholesteremic AgentsApolipoprotein B-100Body Mass IndexCardiovascular DiseasesCholesterol, LDLDose-Response Relationship, DrugDouble-Blind MethodDrug Administration ScheduleEzetimibeFemaleFollow-Up StudiesHumansLipidsalirocumabAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAnticholesteremic AgentsApolipoprotein B-100Cholesterol, LDLEzetimibeLipidsapolipoproteinscardiovascular diseasescholesterol, LDLrisk

Identifiers

PMID27777279
PMCPMC5147039
OpenAlexW2535371675

What Socratic holds

Texttitle and abstract
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

and 4 more above

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.