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Randomized Controlled Trial
. 2021 Dec 1;6(12):1440-1445.
doi: 10.1001/jamacardio.2021.3079.

Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome

Gorav Batra  1   2 , Tatevik Ghukasyan Lakic  1 , Johan Lindbäck  1 , Claes Held  1   2 , Harvey D White  3 , Ralph A H Stewart  3 , Wolfgang Koenig  4   5 , Christopher P Cannon  6 , Andrzej Budaj  7 , Emil Hagström  1   2 , Agneta Siegbahn  1   8 , Lars Wallentin  1   2 ; STABILITY Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome

Gorav Batra et al. JAMA Cardiol. .

Abstract

Importance: Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.

Objective: To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function.

Design, setting, and participants: This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.

Exposures: Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]).

Main outcomes and measures: Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke.

Results: This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]).

Conclusions and relevance: In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Batra reported personal fees from AstraZeneca and Boehringer Ingelheim outside the submitted work. Ms Ghukasyan Lakic and Mr Lindbäck report institutional research grants from GlaxoSmithKline during the conduct of the study. Dr Held reports institutional research grants from GlaxoSmithKline during the conduct of the study; honoraria and research grants from Pfizer; consultant and advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, and Coala Life. Dr White reported grants from Omthera Pharmaceuticals paid to the institution and fees for serving on a steering committee for the STRENGTH trial; grants from American Regent paid to the institution and fees for serving on a steering committee for the HEART-FID study; grants from Eisai paid to the institution and fees for serving on a steering committee for the CAMELLIA-TIMI study; grants from DalCor Pharmaceuticals paid to the institution and fees for serving on a steering committee for the dal-GenE study; grants from CSL Behring paid to the institution and fees for serving on a steering committee for the AEGIS-II study; grants from Sanofi-Aventis Australia Pty Ltd paid to the institution and fees for serving on a steering committee for the SCORED trial and SOLOIST-WHF trial; grants from Esperion Therapeutics paid to the institution and fees for serving on a steering committee for the CLEAR Outcomes study; grants from Eli Lilly and Company to the institution and fees for serving on a steering committee for the ACCELERATE Study; grants from Sanofi-Aventis and Regeneron Pharmaceuticals paid to the institution and fees for serving on a steering committee for the ODYSSEY OUTCOMES trial; grants from National Heart, Lung, and Blood Institute paid to the institution; grants from GlaxoSmithKline paid to the institution; personal fees from Genentech for serving on an advisory board; and personal fees from AstraZeneca for lectures outside the submitted work. Dr Stewart reported grants from GlaxoSmithKline during the conduct of the study. Dr Koenig reported personal fees from AstraZeneca, The Medicines Company, DalCor Pharmaceuticals, Kowa, Amgen, Daiichi Sankyo, Genentech, Novo Nordisk, Esperion Therapeutics, OMEICOS, Lib Therapeutics, Berlin Chemie, Sanofi, and Bristol Myers Squibb; honorarium and personal fees from Novartis; Pfizer, and Corvidia Therapeutics; and nonfinancial support from Abbott, Roche Diagnostics, Beckmann, and Singulex (all for provision of reagents free of charge)outside the submitted work. Dr Cannon reported grants from GlaxoSmithKline for the trial during the conduct of the study; grants from Amgen, Arisaph Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Merck, Novo Nordisk, Pfizer, and Takeda outside the submitted work; personal fees from Aegerion Pharmaceuticals, Alnylam Pharmaceuticals, Amarin, Amgen, Applied Therapeutics, Ascendia, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Corvidia, Eli Lilly and Company, Eisai, GlaxoSmithKline, HLS Therapeutics, Innovent Bio, Lipimedix, Janssen, Kowa, Lexicon, Merck, Pfizer, Rhoshan, Regeneron, and Sanofi outside the submitted work. Dr Budaj reported personal fees/honoraria from GlaxoSmithKline during the conduct of the study and personal fees/honoraria from AstraZeneca, Bristol Myers Squibb/Pfizer, Sanofi-Aventis, Eisai, Novartis, Amgen, and Bayer outside the submitted work. Dr Hagström reports research grants and speaker fees from Amgen and Sanofi and expert committee fees from NovoNordisk. Dr Siegbahn reported institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, and Roche Diagnostics and consulting fees from Olink Proteomics during the conduct of the study and outside the submitted work. Dr Wallentin reports institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, GlaxoSmithKline, Merck, and Roche Diagnostics and consulting fees from Abbott.

Figures

Figure 1.
Figure 1.. Associations Between Continuous IL-6 Concentrations and Outcome Across CKD Strata
Estimated event rates of outcomes across chronic kidney disease (CKD) strata (estimated glomerular filtration rate [eGFR] ≥90, 60-90, and <60 mL/min/1.73 m2) associated with continuous baseline concentrations of interleukin 6 (IL-6) fitted as restricted cubic splines. The P values correspond with the test of the association between outcome and IL-6 (PIL-6), eGFR (PCKD), and the multiplicative eGFR × IL-6 interaction (PInt). The x-axis is presented on a logarithmic scale. Vertical dashed lines represent the 3 sample quartiles. CV indicates cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction.
Figure 2.
Figure 2.. Event Rates for Major Adverse Cardiovascular Events by Chronic Kidney Disease Strata
Event rates for major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) associated with baseline concentrations of interleukin 6 (IL-6) (≥2.0 ng/L and <2.0 ng/L) by chronic kidney disease strata (estimated glomerular filtration rate [eGFR] ≥90, 60-90, and <60 mL/min/1.73 m2).
See this image and copyright information in PMC

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