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

Peter Willeit; Lena Tschiderer; Elias Allara; Kathrin Reuber; Lisa Seekircher; Lu Gao; Ximing Liao; Eva Lonn; Hertzel C Gerstein; Salim Yusuf; Frank P Brouwers; Folkert W Asselbergs; Wiek van Gilst; Sigmund A Anderssen; Diederick E Grobbee; John J P Kastelein; Frank L J Visseren; George Ntaios; Apostolos I Hatzitolios; Christos Savopoulos; Pythia T Nieuwkerk; Erik Stroes; Matthew Walters; Peter Higgins; Jesse Dawson; Paolo Gresele; Giuseppe Guglielmini; Rino Migliacci; Marat Ezhov; Maya Safarova; Tatyana Balakhonova; Eiichi Sato; Mayuko Amaha; Tsukasa Nakamura; Kostas Kapellas; Lisa M Jamieson; Michael Skilton; James A Blumenthal; Alan Hinderliter; Andrew Sherwood; Patrick J Smith; Michiel A van Agtmael; Peter Reiss; Marit G A van Vonderen; Stefan Kiechl; Gerhard Klingenschmid; Matthias Sitzer; Coen D A Stehouwer; Peter J Blankestijn; Michiel L Bots

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

Peter Willeit, Lena Tschiderer, Elias Allara, Kathrin Reuber, Lisa Seekircher, Lu Gao, Ximing Liao, Eva Lonn, Hertzel C Gerstein, Salim Yusuf, Frank P Brouwers, Folkert W Asselbergs, Wiek van Gilst, Sigmund A Anderssen, Diederick E Grobbee, John J P Kastelein, Frank L J Visseren, George Ntaios, Apostolos I Hatzitolios, Christos SavopoulosPythia T Nieuwkerk, Erik Stroes, Matthew Walters, Peter Higgins, Jesse Dawson, Paolo Gresele, Giuseppe Guglielmini, Rino Migliacci, Marat Ezhov, Maya Safarova, Tatyana Balakhonova, Eiichi Sato, Mayuko Amaha, Tsukasa Nakamura, Kostas Kapellas, Lisa M Jamieson, Michael Skilton, James A Blumenthal, Alan Hinderliter, Andrew Sherwood, Patrick J Smith, Michiel A van Agtmael, Peter Reiss, Marit G A van Vonderen, Stefan Kiechl, Gerhard Klingenschmid, Matthias Sitzer, Coen D A Stehouwer, Peter J Blankestijn, Michiel L Bots,

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

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
Early online date	17 Jun 2020
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.120.046361
Publication status	Published - 18 Aug 2020

Keywords

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

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10.1161/CIRCULATIONAHA.120.046361

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Willeit, P., Tschiderer, L., Allara, E., Reuber, K., Seekircher, L., Gao, L., Liao, X., Lonn, E., Gerstein, H. C., Yusuf, S., Brouwers, F. P., Asselbergs, F. W., van Gilst, W., Anderssen, S. A., Grobbee, D. E., Kastelein, J. J. P., Visseren, F. L. J., Ntaios, G., Hatzitolios, A. I. (2020). Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100,667 Patients. Circulation, 142(7), 621-642. https://doi.org/10.1161/CIRCULATIONAHA.120.046361

@article{1d93be6f7ad0471697df8428965cf7b3,

title = "Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: 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, surrogate marker, meta-analysis",

author = "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 Blankestijn, {Peter J} and Bots, {Michiel L}",

note = "Publisher Copyright: {\textcopyright} 2020 American Heart Association, Inc.",

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 & Wilkins",

number = "7",

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Willeit, P, Tschiderer, L, Allara, E, Reuber, K, Seekircher, L, Gao, L, Liao, X, Lonn, E, Gerstein, HC, Yusuf, S, Brouwers, FP, Asselbergs, FW, van Gilst, W, Anderssen, SA, Grobbee, DE, Kastelein, JJP, Visseren, FLJ, Ntaios, G, Hatzitolios, AI, Savopoulos, C, Nieuwkerk, PT, Stroes, E, Walters, M, Higgins, P, Dawson, J, Gresele, P, Guglielmini, G, Migliacci, R, Ezhov, M, Safarova, M, Balakhonova, T, Sato, E, Amaha, M, Nakamura, T, Kapellas, K, Jamieson, LM, Skilton, M, Blumenthal, JA, Hinderliter, A, Sherwood, A, Smith, PJ, van Agtmael, MA, Reiss, P, van Vonderen, MGA, Kiechl, S, Klingenschmid, G, Sitzer, M, Stehouwer, CDA, Blankestijn, PJ, Bots, ML 2020, 'Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: 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

TY - JOUR

T1 - Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk

T2 - Meta-Analysis of 119 Clinical Trials Involving 100,667 Patients

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 - Blankestijn, Peter J

AU - Bots, Michiel L

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 - surrogate marker

KW - meta-analysis

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 -

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

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Keywords

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