Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment

Abstract

International guidelines recommend treatment with statins for patients with preexisting ischemic heart disease to prevent additional cardiovascular events but differ regarding target levels of low-density lipoprotein cholesterol (LDL-C). Trial data on this question are inconclusive and observational data are lacking. OBJECTIVE To assess the relationship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with preexisting ischemic heart disease. DESIGN, SETTING, AND PARTICIPANTS Population-based observational cohort study from 2009 to 2013 using data from a health care organization in Israel covering more than 4.3 million members. Included patients had ischemic heart disease, were aged 30 to 84 years, were treated with statins, and were at least 80% adherent to treatment or, in a sensitivity analysis, at least 50% adherent. Patients with active cancer or metabolic abnormalities were excluded. EXPOSURES Index LDL-C was defined as the first achieved serum LDL-C measure after at least 1 year of statin treatment, grouped as low (Յ70.0 mg/dL), moderate (70.1-100.0 mg/dL), or high (100.1-130.0 mg/dL). MAIN OUTCOMES AND MEASURES Major adverse cardiac events included acute myocardial infarction, unstable angina, stroke, angioplasty, bypass surgery, or all-cause mortality. The hazard ratio of adverse outcomes was estimated using 2 Cox proportional hazards models with low vs moderate and moderate vs high LDL-C, adjusted for confounders and further tested using propensity score matching analysis. RESULTS The cohort with at least 80% adherence included 31 619 patients, for whom the mean (SD) age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking statin treatment. Overall, there were 9035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1000 persons per year). The adjusted incidence of adverse outcomes was not different between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97-1.07; P = .54), but it was lower with moderate vs high LDL-C (HR, 0.89; 95% CI, 0.84-0.94; P < .001). Among 54 884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02-1.10; P = .001) in the low vs moderate groups and 0.87 (95% CI, 0.84-0.91; P = .001) in the moderate vs high groups. CONCLUSIONS AND RELEVANCE Patients with LDL-C levels of 70 to 100 mg/dL taking statins had lower risk of adverse cardiac outcomes compared with those with LDL-C levels between 100 and 130 mg/dL, but no additional benefit was gained by achieving LDL-C of 70 mg/dL or less. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with preexisting heart disease.

The Expected Cardiovascular Benefit of Plasma Cholesterol Lowering with or Without LDL-C Targets in Healthy Individuals at Higher Cardiovascular Risk

“…This finding, however, contrasts with a recent population-based study that reported no additional benefit by achieving LDL-c 70 mg/dL or less in individuals with stable ischemic heart disease taking statins. 20 …”

Real-world cardiovascular disease burden in patients with atherosclerotic cardiovascular disease: a comprehensive systematic literature review

“…Excluding revascularization, the composite MACE rates were 64 in high-risk ASCVD, 148 in ACS, 112 in ischemic stroke and 131 in heart failure cohorts, while multiple event rates were 100, 183, 121 and 191, respectively. Leibowitz et al 24 reported that the first occurrence of MACE (MI, unstable angina, stroke, PCI, CABG or all-cause mortality) per 1000 person-years was 78.1, 71.0, and 81.3 in patients with LDL-C 70 mg/dL, LDL-C 70.1-100.0 mg/dL, and LDL-C 100.1-130.0 mg/dL, respectively, among Israeli patients with prior MACEs and statin therapy. In Huang et al 22 , composite rates (of ACS, stroke, coronary revascularization and CVrelated mortality) in ASCVD patients on high-intensity statins or low-/moderate-intensity statins were 103.1 and 87.0 per 1000 person-years, respectively.…”

Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis

“…Our findings are in line with a recent double-blind, placebo-controlled study ( n = 17,082) reporting a direct relationship between the magnitude of statin-mediated LDL-C reduction and the clinical benefit achieved [11]. However, a previous analysis ( n = 31,619) demonstrated that although patients achieving LDL-C levels of 70–100 mg/dL with statin therapy were at a lower CV risk than those achieving levels of 100–130 mg/dL, no additional benefit was gained by achieving levels ≤70 mg/dL [12]. …”