Inflammation stronger predictor of future MACE in statin-treated CKD patients than LDL-c
Inflammation drives residual risk in chronic kidney disease: a CANTOS substudyLiterature - Ridker PM, Tuttle KR, Perkovic V, et al. - Eur Heart J. 2022 Aug 9;ehac444 [Online ahead of print]. doi: 10.1093/eurheartj/ehac444
Introduction and methods
Despite taking statins, patients with atherosclerosis and CKD have a particularly high risk of recurrent CV events. However, it is not clear what drives the occurrence of MACE in this population: their residual cholesterol risk or their residual inflammatory risk?
Aim of the study
The authors set out to evaluate the relative utility of lipid and inflammatory biomarker levels as predictors of future MACE, CV death, and all-cause mortality in stable atherosclerosis patients on statin therapy who had participated in the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) trial, stratified by eGFR.
In the international CANTOS trial, the effect of IL -1β inhibition with canakinumab versus placebo was investigated in stable coronary artery disease . For the current substudy, data from 9151 statin-treated patients with a history of MI, and hs-CRP >2 mg/L and eGFR >30 mL/min per 1.73 m2 at baseline were used. Irrespective of randomized treatment allocation, participants were divided into two groups based on baseline eGFR (recalculated using the race agnostic CKD-EPI 2021 formula): <60 versus ≥60 mL/min per 1.73 m2. The median follow-up duration was 3.7 years.
The primary analyses focused on LDL-c and hs-CRP, whereas the secondary analyses focused on non–HDL-c and IL-6. In additional secondary analyses, participants were stratified by albumin-to-creatinine ratio (<3 vs. ≥3 mg/mmol), rather than by eGFR. All analyses were adjusted for randomized treatment assignment. To eliminate potential confounding based on treatment allocation, additional sensitivity analyses were performed in patients in the placebo group.
The endpoints were adjudicated incident CV clinical outcomes (including recurrent nonfatal MI, nonfatal stroke, coronary revascularization procedures, and CV death) and adjudicated all-cause mortality.
- Among patients with preserved kidney function at baseline (eGFR ≥ 60 mL/min per 1.73 m2), increasing quartiles of median levels of hs-CRP and LDL-c were positively associated with risk of subsequent MACE. The hazard ratio (HR) comparing the highest with the lowest quartile was 1.45 (95%: 1.22–1.72; P<0.0001) for hs-CRP and 1.64 (95%CI: 1.38–1.95; P<0.0001) for LDL-c.
- In patients with impaired kidney function (eGFR < 60 mL/min per 1.73 m2), increasing quartiles of hs-CRP were also associated with elevated risk of recurrent MACE (HR for highest vs. lowest quartile: 1.50; 95%CI: 1.06–2.13; P=0.021) but increasing quartiles of LDL-c were not (HR for highest vs. lowest quartile: 1.04; 95%CI: 0.76–1.43; P=0.80).
- Similar results were obtained with the secondary analyses: In patients with preserved kidney function, there was a strong association of MACE risk with increasing levels of IL-6 (HR for highest vs. lowest quartile: 2.48; 95%CI: 1.95–3.16; P<0.0001) and non–HDL-c (HR for highest vs. lowest quartile: 1.68; 95%CI: 1.42–1.99; P<0.0001). In patients with impaired kidney function, only IL-6 was associated with this risk (HR for highest vs. lowest quartile: 1.84; 95%CI: 1.01–3.37; P=0.048), not non–HDL-c .
- In patients with impaired kidney function, the predictive utility of hs-CRP and IL-6 for MACE risk remained significant after multivariable adjustment for potential confounders such as age, gender, smoking status, blood pressure, BMI, and diabetes mellitus.
- However, once the eGFR was known, neither LDL-c nor non–HDL-c substantially added to the MACE risk evaluation in the joint-effect analysis.
- The sensitivity analyses of the placebo-only subgroup yielded similar findings, making confounding due to drug allocation unlikely.
CV death risk
- In patients with preserved kidney function, both hs-CRP (HR for highest vs. lowest quartile: 1.98; 95%CI: 1.51–2.16; P<0.0001) and IL-6 (HR for highest vs. lowest quartile: 4.12; 95%CI: 2.64–6.42; P<0.0001) predicted CV death, but LDL-c and non–HDL-c did not.
- In patients with impaired kidney function, only hs-CRP predicted CV mortality (HR for highest vs. lowest quartile: 1.68; 95%CI: 1.07–2.66; P=0.025).
All-cause mortality risk
- In patients with preserved kidney function, hs-CRP (HR for highest vs. lowest quartile: 2.05; 95%CI: 1.65–2.54; P<0.0001) and IL-6 (HR for highest vs. lowest quartile: 4.38; 95%CI: 3.12–6.15; P<0.0001) predicted all-cause mortality.
- Similarly, in patients with impaired kidney function, both hs-CRP (HR for highest vs. lowest quartile: 1.77; 95%CI: 1.23–2.55; P=0.0021) and IL-6 (HR for highest vs. lowest quartile: 2.15; 95%CI: 1.16–3.97; P=0.015) predicted all-cause mortality.
- On the contrary, LDL-c and non–HDL-c were not associated with all-cause mortality in patients with preserved or impaired kidney function.
Stratification by albumin-to-creatinine ratio
- In the additional secondary analyses, similar effects were observed when patients were stratified by the albumin-to-creatinine ratio instead of the eGFR.
In statin-treated, post-MI patients with preserved kidney function, both residual inflammatory risk (as assessed by hs-CRP or IL-6) and residual cholesterol risk (as assessed by LDL-c or non–HDL-c) were associated with risk of MACE. However, in those with impaired kidney function, only residual inflammatory risk predicted MACE. The authors believe their results have implications for CV risk stratification of CKD patients and for the development of novel therapeutic agents that target inflammatory processes in this high-risk patient group.