Association between Non-Lipid Residual Risk Factors and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Pitavastatin: An Observation from the REAL-CAD Study

Abstract

Aims: We aimed to investigate the association between non-lipid residual risk factors and cardiovascular events in patients with stable coronary artery disease (CAD) who achieved low-density lipoprotein cholesterol (LDL-C) ＜100 mg/dL from the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. Methods: The REAL-CAD study was a prospective, multicenter, open-label trial. As a sub-study, we examined the prognostic impact of non-lipid residual risk factors, including blood pressure, glucose level, and renal function, in patients who achieved LDL-C ＜100 mg/dL at 6 months after pitavastatin therapy. Each risk factor was classified according to severity. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, and unstable angina requiring emergency hospitalization. Results: Among 8,743 patients, the mean age was 68±8.2 years, and the mean LDL-C level was 84.4±18 mg/dL. After adjusting for the effects of confounders, an estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m 2 showed the highest risk of the primary outcome (hazard ratio [HR] 1.92; 95% confidence interval [CI] 1.45-2.53). The combination of eGFR ≤ 60 and hemoglobin A1c (HbA1c) ≥ 6.0% also showed the highest risk of all-cause death (HR, 2.42; 95% CI, 1.72-3.41). Conclusions: In patients with stable CAD treated with pitavastatin and who achieved guidelines-directed levels of LDL-C, eGFR and HbA1c were independently associated with adverse events, suggesting that renal function and glycemic control could be residual non-lipid therapeutic targets after statin therapy.

The Worst Combination for Coronary Artery Disease Under Strong-Statin Therapy Is Chronic Kidney Disease and Diabetes ― Non-Lipid Residual Risk Assessment From the REAL-CAD Study ―

“…7 Kamiya et al reported an eGFR ≤60 mL/min/1.73 m 2 showed the highest risk of the primary outcome, and the combination of eGFR ≤60 and hemoglobin A1c (HbA1c) ≥6.0% showed the highest risk of all-cause death among 8,743 patients. 8 In this issue of the Journal, Higuma et al 9 use classification and regression tree analysis for combined risk factors to determine which comorbidities, or combination of comorbidities, best predicted cardiovascular events in 11,141 patients after excluding 1,272 patients because of missing data. They found a significantly worse prognosis at the primary endpoint in the eGFR ≤60 group, and the combination of eGFR ≤60 and HbA1c ≥6.0 was the worst.…”

Residual Cardiovascular Risk Determined through Posthoc Analysis of the REAL-CAD Trial

“…In the CANTOS trial, the use of the IL-1β inhibitor canakinumab reduced the incidence of cardiovascular diseases by improving inflammation without affecting lipid parameters 6) .However, residual risk factors unrelated to lipids remain a relatively unexplored area. The REAL-CAD trial, a randomized controlled study, compared highdose pitavastatin therapy with low-dose therapy in approximately 13,000 Japanese patients with stable CAD, demonstrating that high-dose statin therapy effectively and safely reduced major adverse cardiovascular events (MACEs).In this study, Kamiya et al performed a posthoc analysis of the REAL-CAD trial by selecting the cases of patients with stable CAD from the trial who had achieved LDL-C levels below the JAS guidelinerecommended threshold of 100 mg/dL and identified eGFR and HbA1c as integral lipid-independent residual risk factors 7) .This investigation, which explored residual risk…”

“…In this study, Kamiya et al performed a posthoc analysis of the REAL-CAD trial by selecting the cases of patients with stable CAD from the trial who had achieved LDL-C levels below the JAS guidelinerecommended threshold of 100 mg/dL and identified eGFR and HbA1c as integral lipid-independent residual risk factors 7) .…”