Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation)

Abstract

Objectives: This study sought to assess the independent effect of high-density lipoprotein-cholesterol (HDL-C) level on cardiovascular risk in patients with stable ischemic heart disease (SIHD) who were receiving optimal medical therapy (OMT).

Background: Although low HDL-C level is a powerful and independent predictor of cardiovascular risk, recent data suggest that this may not apply when low-density lipoprotein-cholesterol (LDL-C) is reduced to optimal levels using intensive statin therapy.

Methods: We performed a post-hoc analysis in 2,193 men and women with SIHD from the COURAGE trial. The primary outcome measure was the composite of death from any cause or nonfatal myocardial infarction (MI). The independent association between HDL-C levels measured after 6 months on OMT and the rate of cardiovascular events after 4 years was assessed. Similar analyses were performed separately in subjects with LDL-C levels below 70 mg/dl (1.8 mmol/l).

Results: In the overall population, the rate of death/MI was 33% lower in the highest HDL-C quartile as compared with the lowest quartile, with quartile of HDL-C being a significant, independent predictor of death/MI (p = 0.05), but with no interaction for LDL-C category (p = 0.40). Among subjects with LDL-C levels <70 mg/dl, those in the highest quintile of HDL-C had a 65% relative risk reduction in death or MI as compared with the lowest quintile, with HDL-C quintile demonstrating a significant, inverse predictive effect (p = 0.02).

Conclusions: In this post-hoc analysis, patients with SIHD continued to experience incremental cardiovascular risk associated with low HDL-C levels despite OMT during long-term follow-up. This relationship persisted and appeared more prominent even when LDL-C was reduced to optimal levels with intensive dyslipidemic therapy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; NCT00007657).

Keywords: ACS; ATP; Adult Treatment Panel; BMI; CETP; HDL cholesterol; HDL-C; LDL-C; MI; OMT; PCI; SIHD; acute coronary syndrome(s); body mass index; cholesteryl ester transfer protein; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; myocardial infarction; optimal medical therapy; percutaneous coronary intervention; residual risk; stable ischemic heart disease.

Figure 1. Multivariate Analysis of the Relationship Between Death or MI and Quartiles of HDL Cholesterol

Hazard ratios are adjusted for age, sex, body mass index, hypertension, diabetes, current smoking, and triglycerides, and use lowest quartile (Q1) as referent. CI = confidence interval; HDL = high-density lipoprotein; MI = myocardial infarction.

Figure 2. Relationship Between HDL-C Quartiles and Death or MI Across Categories of LDL-C

The effect of HDL-C quartile on death or MI was independent, with no apparent interaction with LDL-C category (p = 0.40). LDL = Low-density lipoprotein; other abbreviations as in Figure 1.

Figure 3. Multivariate Analysis of the Relationship Between Death or MI and Quintiles of HDL-C Among Patients With LDL Cholesterol <70 mg/dl

Hazard ratios are adjusted for age, sex, body mass index, hypertension, diabetes, current smoking, and triglycerides, and use lowest quintile (Q1) as referent. Abbreviations as in Figures 1 and 2.

Figure 4. Kaplan-Meier Curves for Overall Trial Population

Expected freedom from death or myocardial infarction across quartiles of LDL-C/HDL-C ratio (Q1–Q4) at 6 months. Hazard ratios are adjusted for age, sex, body mass index, hypertension, diabetes, current smoking, and triglycerides, and use the lowest quartile (Q1) as referent. Abbreviations as in Figures 1 and 2.