Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study

Toralph Ruge, Axel Carlsson, Erik Kjøller, Jørgen Hilden, Hans Jørn Kolmos, Ahmed Sajadieh, Jens Kastrup, Gorm Boje Jensen, Anders Larsson, Christoph Nowak, Janus Christian Jakobsen, Per Winkel, Christian Nyfeldt Gluud, Johan Ärnlöv

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Background and aims: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03–1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00–1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). Conclusions: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

OriginalsprogEngelsk
TidsskriftAtherosclerosis
Vol/bind284
Sider (fra-til)202-208
ISSN0021-9150
DOI
StatusUdgivet - 1. maj 2019

Fingeraftryk

Endostatins
Clarithromycin
Serum
Placebos
Random Allocation
Glomerular Filtration Rate
Proportional Hazards Models
Randomized Controlled Trials

Citer dette

Ruge, Toralph ; Carlsson, Axel ; Kjøller, Erik ; Hilden, Jørgen ; Kolmos, Hans Jørn ; Sajadieh, Ahmed ; Kastrup, Jens ; Jensen, Gorm Boje ; Larsson, Anders ; Nowak, Christoph ; Christian Jakobsen, Janus ; Winkel, Per ; Gluud, Christian Nyfeldt ; Ärnlöv, Johan . / Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study. I: Atherosclerosis. 2019 ; Bind 284. s. 202-208.
@article{ee327846c795416db064f185ad3406f3,
title = "Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study",
abstract = "Background and aims: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95{\%} CI 1.03–1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95{\%} CI 1.00–1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1{\%}). Conclusions: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.",
keywords = "Cardiovascular, Endostatin, Epidemiology, Extracellular matrix, Mortality",
author = "Toralph Ruge and Axel Carlsson and Erik Kj{\o}ller and J{\o}rgen Hilden and Kolmos, {Hans J{\o}rn} and Ahmed Sajadieh and Jens Kastrup and Jensen, {Gorm Boje} and Anders Larsson and Christoph Nowak and {Christian Jakobsen}, Janus and Per Winkel and Gluud, {Christian Nyfeldt} and Johan {\"A}rnl{\"o}v",
year = "2019",
month = "5",
day = "1",
doi = "10.1016/j.atherosclerosis.2019.02.031",
language = "English",
volume = "284",
pages = "202--208",
journal = "Atherosclerosis",
issn = "0021-9150",
publisher = "Elsevier",

}

Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study. / Ruge, Toralph; Carlsson, Axel; Kjøller, Erik; Hilden, Jørgen; Kolmos, Hans Jørn; Sajadieh, Ahmed; Kastrup, Jens; Jensen, Gorm Boje; Larsson, Anders; Nowak, Christoph; Christian Jakobsen, Janus; Winkel, Per; Gluud, Christian Nyfeldt; Ärnlöv, Johan .

I: Atherosclerosis, Bind 284, 01.05.2019, s. 202-208.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Circulating endostatin as a risk factor for cardiovascular events in patients with stable coronary heart disease: A CLARICOR trial sub-study

AU - Ruge, Toralph

AU - Carlsson, Axel

AU - Kjøller, Erik

AU - Hilden, Jørgen

AU - Kolmos, Hans Jørn

AU - Sajadieh, Ahmed

AU - Kastrup, Jens

AU - Jensen, Gorm Boje

AU - Larsson, Anders

AU - Nowak, Christoph

AU - Christian Jakobsen, Janus

AU - Winkel, Per

AU - Gluud, Christian Nyfeldt

AU - Ärnlöv, Johan

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background and aims: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03–1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00–1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). Conclusions: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

AB - Background and aims: Raised levels of serum endostatin, a biologically active fragment of collagen XVIII, have been observed in patients with ischemic heart disease but association with incident cardiovascular events in patients with stable coronary heart disease is uncertain. Methods: The CLARICOR-trial is a randomized, placebo-controlled trial of stable coronary heart disease patients evaluating 14-day treatment with clarithromycin. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease or all-cause mortality. In the present sub-study using 10-year follow-up data, we investigated associations between serum endostatin at entry (randomization) and the composite outcome and its components during follow-up. The placebo group was used as discovery sample (1204 events, n = 1998) and the clarithromycin-treated group as replication sample (1220 events, n = 1979). Results: In Cox regression models adjusting for cardiovascular risk factors, glomerular filtration rate, and current pharmacological treatment, higher serum endostatin was associated with an increased risk of the composite outcome in the discovery sample (hazard ratio per standard deviation increase 1.11, 95% CI 1.03–1.19, p = 0.004), but slightly weaker and not statistically significant in the replication sample (hazard ratio 1.06, 95% CI 1.00–1.14, p = 0.06). In contrast, strong and consistent associations were found between endostatin and cardiovascular and all-cause mortality in all multivariable models and sub-samples. Addition of endostatin to a model with established cardiovascular risk factors provided no substantial improvement of risk prediction (<1%). Conclusions: Raised levels of serum endostatin might be associated with cardiovascular events in patients with stable coronary heart disease. The clinical utility of endostatin measurements remains to be established.

KW - Cardiovascular

KW - Endostatin

KW - Epidemiology

KW - Extracellular matrix

KW - Mortality

U2 - 10.1016/j.atherosclerosis.2019.02.031

DO - 10.1016/j.atherosclerosis.2019.02.031

M3 - Journal article

C2 - 30959314

VL - 284

SP - 202

EP - 208

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

ER -