Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients

PROG-IMT and the Proof-ATHERO Study Groups; Heiko Uthoff; Zhi Yong Zou; Ana R. Cunha; Mario F. Neves; Miles D. Witham; Hyun Woong Park; Moo Sik Lee; Jang Ho Bae; Enrique Bernal; Kristian Wachtell; Sverre E. Kjeldsen; Michael H. Olsen; David Preiss; Naveed Sattar; Edith Beishuizen; Menno V. Huisman; Mark A. Espeland; Caroline Schmidt; Stefan Agewall; Ercan Ok; Gülay Aşçi; Peter J. Blankestijn; Michiel L. Bots; Michael J. Sweeting; Simon G. Thompson; Matthias W. Lorenz

doi:10.1161/CIRCULATIONAHA.120.046361

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients

PROG-IMT and the Proof-ATHERO Study Groups
, Heiko Uthoff
, Zhi Yong Zou
, Ana R. Cunha
, Mario F. Neves
, Miles D. Witham
, Hyun Woong Park
, Moo Sik Lee
, Jang Ho Bae
, Enrique Bernal
, Kristian Wachtell
, Sverre E. Kjeldsen
, Michael H. Olsen
, David Preiss
, Naveed Sattar
, Edith Beishuizen
, Menno V. Huisman
, Mark A. Espeland
, Caroline Schmidt
, Stefan Agewall

Ercan Ok, Gülay Aşçi, Peter J. Blankestijn, Michiel L. Bots, Michael J. Sweeting, Simon G. Thompson, Matthias W. Lorenz

Innsbruck Medical University
University of Cambridge
Goethe University Frankfurt
McMaster University
Hamilton Health Sciences
Haga Ziekenhuis
University Medical Center Utrecht
University of Groningen, University Medical Center Groningen
Norwegian School of Sport Sciences
University of Thessaly
Aristotle University of Thessaloniki
University of Glasgow
University of Perugia
Division of Internal Medicine
RAS - USSR Cardiology Research Center
Division of Nephrology, Japan
University of Adelaide
University of Sydney
Duke University
University of North Carolina at Chapel Hill
Vrije Universiteit Amsterdam
Department of Internal Medicine
VASCage GmbH, Innsbruck, Austria
Department of Neurology, Herford, Germany
Maastricht University
Imagelabonline & Cardiovascular
Utrecht University
University of Groningen
University of Amsterdam
Cortona Hospital
Shinmatsudo Central General Hospital
Medical Centre Leeuwarden
VASCage GmbH
Klinikum Herford
University of Basel
Peking University
Universidade do Estado do Rio de Janeiro
Newcastle upon Tyne Hospitals NHS Foundation Trust
Gyeongsang National University
Konyang University
Servicio Murciano de Salud
University of Oslo
University of Southern Denmark
University of Oxford
HMC+ (Bronovo)
Veterinary and Life Sciences
Leiden University
Wake Forest University
University of Gothenburg
Ege University
Imagelabonline and Cardiovascular
University of Leicester

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Original language	English
Pages (from-to)	621-642
Number of pages	22
Journal	Circulation
Volume	142
Issue number	7
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.120.046361
Publication status	Published - 18 Aug 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

cardiovascular disease
carotid intima-media thickness
clinical trials as topic
meta-analysis
surrogate marker

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PROG-IMT and the Proof-ATHERO Study Groups, Uthoff, H., Zou, Z. Y., Cunha, A. R., Neves, M. F., Witham, M. D., Park, H. W., Lee, M. S., Bae, J. H., Bernal, E., Wachtell, K., Kjeldsen, S. E., Olsen, M. H., Preiss, D., Sattar, N., Beishuizen, E., Huisman, M. V., Espeland, M. A., Schmidt, C., ... Lorenz, M. W. (2020). Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients. Circulation, 142(7), 621-642. https://doi.org/10.1161/CIRCULATIONAHA.120.046361

@article{b0433e3b4b9b494bb40b91b805f362db,

title = "Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients",

abstract = "BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42\% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95\% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.",

keywords = "cardiovascular disease, carotid intima-media thickness, clinical trials as topic, meta-analysis, surrogate marker",

author = "\{PROG-IMT and the Proof-ATHERO Study Groups\} and Peter Willeit and Lena Tschiderer and Elias Allara and Kathrin Reuber and Lisa Seekircher and Lu Gao and Ximing Liao and Eva Lonn and Gerstein, \{Hertzel C.\} and Salim Yusuf and Brouwers, \{Frank P.\} and Asselbergs, \{Folkert W.\} and \{van Gilst\}, Wiek and Anderssen, \{Sigmund A.\} and Grobbee, \{Diederick E.\} and Kastelein, \{John J. P.\} and Visseren, \{Frank L. J.\} and George Ntaios and Hatzitolios, \{Apostolos I.\} and Christos Savopoulos and Nieuwkerk, \{Pythia T.\} and Erik Stroes and Matthew Walters and Peter Higgins and Jesse Dawson and Paolo Gresele and Giuseppe Guglielmini and Rino Migliacci and Marat Ezhov and Maya Safarova and Tatyana Balakhonova and Eiichi Sato and Mayuko Amaha and Tsukasa Nakamura and Kostas Kapellas and Jamieson, \{Lisa M.\} and Michael Skilton and Blumenthal, \{James A.\} and Alan Hinderliter and Andrew Sherwood and Smith, \{Patrick J.\} and \{van Agtmael\}, \{Michiel A.\} and Peter Reiss and \{van Vonderen\}, \{Marit G. A.\} and Stefan Kiechl and Gerhard Klingenschmid and Matthias Sitzer and Stehouwer, \{Coen D. A.\} and \{de Groot\}, Eric and Grooteman, \{Muriel P. C.\} and Heiko Uthoff and Zou, \{Zhi Yong\} and Cunha, \{Ana R.\} and Neves, \{Mario F.\} and Witham, \{Miles D.\} and Park, \{Hyun Woong\} and Lee, \{Moo Sik\} and Bae, \{Jang Ho\} and Enrique Bernal and Kristian Wachtell and Kjeldsen, \{Sverre E.\} and Olsen, \{Michael H.\} and David Preiss and Naveed Sattar and Edith Beishuizen and Huisman, \{Menno V.\} and Espeland, \{Mark A.\} and Caroline Schmidt and Stefan Agewall and Ercan Ok and G{\"u}lay A{\c s}{\c c}i and Blankestijn, \{Peter J.\} and Bots, \{Michiel L.\} and Sweeting, \{Michael J.\} and Thompson, \{Simon G.\} and Lorenz, \{Matthias W.\}",

year = "2020",

month = aug,

day = "18",

doi = "10.1161/CIRCULATIONAHA.120.046361",

language = "English",

volume = "142",

pages = "621--642",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "7",

}

PROG-IMT and the Proof-ATHERO Study Groups, Uthoff, H, Zou, ZY, Cunha, AR, Neves, MF, Witham, MD, Park, HW, Lee, MS, Bae, JH, Bernal, E, Wachtell, K, Kjeldsen, SE, Olsen, MH, Preiss, D, Sattar, N, Beishuizen, E, Huisman, MV, Espeland, MA, Schmidt, C, Agewall, S, Ok, E, Aşçi, G, Blankestijn, PJ, Bots, ML, Sweeting, MJ, Thompson, SG & Lorenz, MW 2020, 'Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients', Circulation, vol. 142, no. 7, pp. 621-642. https://doi.org/10.1161/CIRCULATIONAHA.120.046361

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients. / PROG-IMT and the Proof-ATHERO Study Groups; Uthoff, Heiko; Zou, Zhi Yong et al.
In: Circulation, Vol. 142, No. 7, 18.08.2020, p. 621-642.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients

T2 - Meta-Analysis of 119 clinical trials involving 100 667 patients

AU - PROG-IMT and the Proof-ATHERO Study Groups

AU - Willeit, Peter

AU - Tschiderer, Lena

AU - Allara, Elias

AU - Reuber, Kathrin

AU - Seekircher, Lisa

AU - Gao, Lu

AU - Liao, Ximing

AU - Lonn, Eva

AU - Gerstein, Hertzel C.

AU - Yusuf, Salim

AU - Brouwers, Frank P.

AU - Asselbergs, Folkert W.

AU - van Gilst, Wiek

AU - Anderssen, Sigmund A.

AU - Grobbee, Diederick E.

AU - Kastelein, John J. P.

AU - Visseren, Frank L. J.

AU - Ntaios, George

AU - Hatzitolios, Apostolos I.

AU - Savopoulos, Christos

AU - Nieuwkerk, Pythia T.

AU - Stroes, Erik

AU - Walters, Matthew

AU - Higgins, Peter

AU - Dawson, Jesse

AU - Gresele, Paolo

AU - Guglielmini, Giuseppe

AU - Migliacci, Rino

AU - Ezhov, Marat

AU - Safarova, Maya

AU - Balakhonova, Tatyana

AU - Sato, Eiichi

AU - Amaha, Mayuko

AU - Nakamura, Tsukasa

AU - Kapellas, Kostas

AU - Jamieson, Lisa M.

AU - Skilton, Michael

AU - Blumenthal, James A.

AU - Hinderliter, Alan

AU - Sherwood, Andrew

AU - Smith, Patrick J.

AU - van Agtmael, Michiel A.

AU - Reiss, Peter

AU - van Vonderen, Marit G. A.

AU - Kiechl, Stefan

AU - Klingenschmid, Gerhard

AU - Sitzer, Matthias

AU - Stehouwer, Coen D. A.

AU - de Groot, Eric

AU - Grooteman, Muriel P. C.

AU - Uthoff, Heiko

AU - Zou, Zhi Yong

AU - Cunha, Ana R.

AU - Neves, Mario F.

AU - Witham, Miles D.

AU - Park, Hyun Woong

AU - Lee, Moo Sik

AU - Bae, Jang Ho

AU - Bernal, Enrique

AU - Wachtell, Kristian

AU - Kjeldsen, Sverre E.

AU - Olsen, Michael H.

AU - Preiss, David

AU - Sattar, Naveed

AU - Beishuizen, Edith

AU - Huisman, Menno V.

AU - Espeland, Mark A.

AU - Schmidt, Caroline

AU - Agewall, Stefan

AU - Ok, Ercan

AU - Aşçi, Gülay

AU - Blankestijn, Peter J.

AU - Bots, Michiel L.

AU - Sweeting, Michael J.

AU - Thompson, Simon G.

AU - Lorenz, Matthias W.

PY - 2020/8/18

Y1 - 2020/8/18

N2 - BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

AB - BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

KW - cardiovascular disease

KW - carotid intima-media thickness

KW - clinical trials as topic

KW - meta-analysis

KW - surrogate marker

UR - https://www.scopus.com/pages/publications/85089708643

U2 - 10.1161/CIRCULATIONAHA.120.046361

DO - 10.1161/CIRCULATIONAHA.120.046361

M3 - Article

C2 - 32546049

SN - 0009-7322

VL - 142

SP - 621

EP - 642

JO - Circulation

JF - Circulation

IS - 7

ER -

PROG-IMT and the Proof-ATHERO Study Groups, Uthoff H, Zou ZY, Cunha AR, Neves MF, Witham MD et al. Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients. Circulation. 2020 Aug 18;142(7):621-642. doi: 10.1161/CIRCULATIONAHA.120.046361

Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients: Meta-Analysis of 119 clinical trials involving 100 667 patients

Abstract

UN SDGs

Keywords

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