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Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial

Summary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE i... Full description

Journal Title: The Lancet (British edition) 2011, Vol.378 (9802), p.1547-1559
Main Author: Fayad, Zahi A, Prof
Other Authors: Mani, Venkatesh, PhD , Woodward, Mark, Prof , Kallend, David, MB BS , Abt, Markus, PhD , Burgess, Tracy, MSc , Fuster, Valentin, Prof , Ballantyne, Christie M, Prof , Stein, Evan A, Prof , Tardif, Jean-Claude, Prof , Rudd, James H F, MD , Farkouh, Michael E, MD , Tawakol, Ahmed, MD
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: Kidlington: Elsevier Ltd
ID: ISSN: 0140-6736
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4151875
title: Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
format: Article
creator:
  • Fayad, Zahi A, Prof
  • Mani, Venkatesh, PhD
  • Woodward, Mark, Prof
  • Kallend, David, MB BS
  • Abt, Markus, PhD
  • Burgess, Tracy, MSc
  • Fuster, Valentin, Prof
  • Ballantyne, Christie M, Prof
  • Stein, Evan A, Prof
  • Tardif, Jean-Claude, Prof
  • Rudd, James H F, MD
  • Farkouh, Michael E, MD
  • Tawakol, Ahmed, MD
subjects:
  • Adolescent
  • Adult
  • Aged
  • Amides
  • Anticholesteremic Agents
  • Anticholesteremic Agents - administration & dosage
  • Article
  • Atherosclerosis
  • Atherosclerosis (general aspects, experimental research)
  • Biological and medical sciences
  • Biomedical research
  • Blind Method
  • Blood and lymphatic vessels
  • Blood pressure
  • carbohydrates (lipids)
  • Cardiology. Vascular system
  • Cardiovascular disease
  • Cardiovascular diseases
  • Cholesterol
  • Clinical medicine
  • clinical trials
  • Confidence Intervals
  • Coronary Artery Disease
  • Coronary Artery Disease - diagnosis
  • Coronary Artery Disease - prevention & control
  • Coronary Stenosis
  • Coronary Stenosis - diagnosis
  • Coronary Stenosis - prevention & control
  • Diagnosis
  • Diagnostic Imaging
  • Diagnostic Imaging - methods
  • Dose
  • Dose-Response Relationship, Drug
  • Double
  • Double-Blind Method
  • Drug
  • Drug Administration Schedule
  • Drug therapy
  • Drug Toxicity
  • Drug-Related Side Effects and Adverse Reactions
  • Emission Tomography
  • enlargement
  • Esters
  • Female
  • Follow
  • Follow-Up Studies
  • General aspects
  • Health aspects
  • Humans
  • Hypercholesterolemia
  • Hypercholesterolemia - diagnosis
  • Hypercholesterolemia - drug therapy
  • Internal Medicine
  • lipids (amino acids
  • Lipoproteins
  • Magnetic Resonance Imaging
  • Magnetic Resonance Imaging - methods
  • Male
  • Medical research
  • Medical sciences
  • Medicine
  • Middle Aged
  • Mortality
  • peptides
  • Positron
  • Positron-Emission Tomography - methods
  • Proteins
  • Reference Values
  • Response Relationship
  • Risk Assessment
  • Side effects
  • Sulfhydryl Compounds
  • Sulfhydryl Compounds - administration & dosage
  • Treatment Outcome
  • Up Studies
  • Young Adult
ispartof: The Lancet (British edition), 2011, Vol.378 (9802), p.1547-1559
description: Summary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and18 F-fluorodeoxyglucose (18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the r
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
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titleSafety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
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creatorFayad, Zahi A, Prof ; Mani, Venkatesh, PhD ; Woodward, Mark, Prof ; Kallend, David, MB BS ; Abt, Markus, PhD ; Burgess, Tracy, MSc ; Fuster, Valentin, Prof ; Ballantyne, Christie M, Prof ; Stein, Evan A, Prof ; Tardif, Jean-Claude, Prof ; Rudd, James H F, MD ; Farkouh, Michael E, MD ; Tawakol, Ahmed, MD
creatorcontribFayad, Zahi A, Prof ; Mani, Venkatesh, PhD ; Woodward, Mark, Prof ; Kallend, David, MB BS ; Abt, Markus, PhD ; Burgess, Tracy, MSc ; Fuster, Valentin, Prof ; Ballantyne, Christie M, Prof ; Stein, Evan A, Prof ; Tardif, Jean-Claude, Prof ; Rudd, James H F, MD ; Farkouh, Michael E, MD ; Tawakol, Ahmed, MD ; for the dal-PLAQUE Investigators ; dal-PLAQUE Investigators
descriptionSummary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and18 F-fluorodeoxyglucose (18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. Funding F Hoffmann-La Roche Ltd.
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subjectAdolescent ; Adult ; Aged ; Amides ; Anticholesteremic Agents ; Anticholesteremic Agents - administration & dosage ; Article ; Atherosclerosis ; Atherosclerosis (general aspects, experimental research) ; Biological and medical sciences ; Biomedical research ; Blind Method ; Blood and lymphatic vessels ; Blood pressure ; carbohydrates (lipids) ; Cardiology. Vascular system ; Cardiovascular disease ; Cardiovascular diseases ; Cholesterol ; Clinical medicine ; clinical trials ; Confidence Intervals ; Coronary Artery Disease ; Coronary Artery Disease - diagnosis ; Coronary Artery Disease - prevention & control ; Coronary Stenosis ; Coronary Stenosis - diagnosis ; Coronary Stenosis - prevention & control ; Diagnosis ; Diagnostic Imaging ; Diagnostic Imaging - methods ; Dose ; Dose-Response Relationship, Drug ; Double ; Double-Blind Method ; Drug ; Drug Administration Schedule ; Drug therapy ; Drug Toxicity ; Drug-Related Side Effects and Adverse Reactions ; Emission Tomography ; enlargement ; Esters ; Female ; Follow ; Follow-Up Studies ; General aspects ; Health aspects ; Humans ; Hypercholesterolemia ; Hypercholesterolemia - diagnosis ; Hypercholesterolemia - drug therapy ; Internal Medicine ; lipids (amino acids ; Lipoproteins ; Magnetic Resonance Imaging ; Magnetic Resonance Imaging - methods ; Male ; Medical research ; Medical sciences ; Medicine ; Middle Aged ; Mortality ; peptides ; Positron ; Positron-Emission Tomography - methods ; Proteins ; Reference Values ; Response Relationship ; Risk Assessment ; Side effects ; Sulfhydryl Compounds ; Sulfhydryl Compounds - administration & dosage ; Treatment Outcome ; Up Studies ; Young Adult
ispartofThe Lancet (British edition), 2011, Vol.378 (9802), p.1547-1559
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2Woodward, Mark, Prof
3Kallend, David, MB BS
4Abt, Markus, PhD
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6Fuster, Valentin, Prof
7Ballantyne, Christie M, Prof
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9Tardif, Jean-Claude, Prof
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11Farkouh, Michael E, MD
12Tawakol, Ahmed, MD
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0Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
1The Lancet (British edition)
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descriptionSummary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and18 F-fluorodeoxyglucose (18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. Funding F Hoffmann-La Roche Ltd.
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titleSafety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
authorFayad, Zahi A, Prof ; Mani, Venkatesh, PhD ; Woodward, Mark, Prof ; Kallend, David, MB BS ; Abt, Markus, PhD ; Burgess, Tracy, MSc ; Fuster, Valentin, Prof ; Ballantyne, Christie M, Prof ; Stein, Evan A, Prof ; Tardif, Jean-Claude, Prof ; Rudd, James H F, MD ; Farkouh, Michael E, MD ; Tawakol, Ahmed, MD
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18Cholesterol
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71Sulfhydryl Compounds
72Sulfhydryl Compounds - administration & dosage
73Treatment Outcome
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75Young Adult
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jtitleThe Lancet (British edition)
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Fayad, Zahi A, Prof
1Mani, Venkatesh, PhD
2Woodward, Mark, Prof
3Kallend, David, MB BS
4Abt, Markus, PhD
5Burgess, Tracy, MSc
6Fuster, Valentin, Prof
7Ballantyne, Christie M, Prof
8Stein, Evan A, Prof
9Tardif, Jean-Claude, Prof
10Rudd, James H F, MD
11Farkouh, Michael E, MD
12Tawakol, Ahmed, MD
aucorp
0for the dal-PLAQUE Investigators
1dal-PLAQUE Investigators
formatjournal
genrearticle
ristypeJOUR
atitleSafety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial
jtitleThe Lancet (British edition)
addtitleLancet
date2011
risdate2011
volume378
issue9802
spage1547
epage1559
pages1547-1559
issn0140-6736
eissn1474-547X
codenLANCAO
abstractSummary Background Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints. Methods In this phase 2b, double-blind, multicentre trial, patients (aged 18–75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and18 F-fluorodeoxyglucose (18 F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00655473. Findings 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was −4·01 mm2 (90% CI −7·23 to −0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (–7·3 [90% CI −13·5 to −0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups. Interpretation Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed. Funding F Hoffmann-La Roche Ltd.
copKidlington
pubElsevier Ltd
pmid21908036
doi10.1016/S0140-6736(11)61383-4
oafree_for_read