Congestive heart failure is associated with lipoprotein components in statin-treated patients with coronary heart disease

Abstract

Background

Very few, if any, studies have assessed the ability of apolipoproteins to predict new-onset of congestive heart failure (HF) in statin-treated patients with coronary heart disease (CHD).

Aims

To employ the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL) study database to assess the association of on-treatment lipoprotein components with prediction of HF events and to compare their predictive value with that of established risk factors such as hypertension and diabetes.

Methods

We used Cox regression models to study the relationships between on-treatment levels of apolipoproteins A1 and B to subsequent HF. Chi square information value from the log likelihood was used to compare the predictive value of lipoprotein components with established risk factors of HF.

Findings

In the IDEAL study, on-treatment apolipoproteins proved to be associated with the occurrence of new-onset HF. Variables related to low-density lipoprotein cholesterol (LDL-C) carried less predictive information than those related to high-density lipoprotein cholesterol (HDL-C), and apoA-1 was the single variable most strongly associated with HF. LDL-C was less predictive than both non-HDL-C (total cholesterol minus HDL-C) and apoB. The ratio of apoB to apoA-1 was most strongly related to HF after adjustment for potential confounders, among which diabetes had a stronger correlation with HF than did hypertension. ApoB/apoA-1 carried approximately 2.2 times more of the statistical information value than that of diabetes. Calculation of the net reclassification improvement index revealed that about 3.7% of the patients had to be reclassified into more correct categories of risk once apoB/apoA-1 was added to the adjustment factors. The reduction in risk by intensive lipid-lowering treatment as compared to usual-dose simvastatin was well predicted by the difference in apoB/apoA-1 on-treatment levels.

Interpretation

The on-treatment ratio of apoB/apoA-1 was the strongest predictor of HF in CHD patients of both IDEAL treatment arms combined, mostly driven by the strong association with apoA-1, whereas LDL-C and non-HDL-C were less able to predict HF outcome. The predictive information value contained within apoB/apoA-1 was about 2.2 times more than that of diabetes. Between-treatment group differences in HF were to a significant extent explained by on-treatment differences in apoB/apoA-1, mostly through the changes in apoB. We argue therefore, on-treatment lipoprotein components contribute to the overall future risk of HF in statin-treated patients with CHD.

Introduction

The prevalence of congestive heart failure (HF) in elderly patients with coronary heart disease (CHD) is increasing and therefore constitutes a burden to health care systems as populations age around the world [1]. Common causes of the myocardial damage underlying HF include CHD, diabetes, and hypertension [1], [2].

In statin-treated patients with CHD, the Treating to New Targets (TNT) study showed that new episodes of HF were reduced by high-dose atorvastatin treatment compared with moderate-dose atorvastatin, but only in patients with HF at baseline [3]. In addition, in the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study, we found that HF was significantly reduced in the high-dose atorvastatin treatment group compared with the simvastatin usual care group when HF at baseline was taken into account [4]. In the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA), however, no such relationship was found [5], whereas the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) could not demonstrate a reduced incidence of major cardiovascular end points by statin treatment in elderly patients with moderate to severe systolic HF [6].

In observational studies, relationships between lipoprotein components and development of death or HF have been mixed, albeit affected by degree of HF severity, length of follow-up, and etiology of HF. Horwich et al. reported an inverse relationship between serum total cholesterol (TC) and mortality in patients with advanced heart failure [7], whereas Dhingra et al. found no association of either TC or high-density lipoprotein cholesterol (HDL-C) with incident heart failure in the Physicians Health Study [8]. In 117 patients with nonischemic heart failure, Iwaoka et al. found that apolipoprotein A-1 (apoA-1) was inversely and independently related to time to first occurrence of a combined end point consisting of death, cardiac death and hospitalization for worsening of heart failure during a 3-year follow-up [9]. Ingelsson et al. reported from a 29-year follow-up study of 2321 healthy middle-aged men that the ratio of apolipoprotein B (apoB) to apoA-1 was highly significantly related to development of heart failure [10]. Probably based on these conflicting results lipoprotein abnormalities are not a focus in the treatment of patients with CHD and mild to moderate heart failure [11].

In IDEAL we have reported that on-treatment lipoprotein components were predictive of major coronary events as well as of any cardiovascular events [12]. Our aims here are to report on the relationship between lipoprotein components and risk of HF in the combined study group and to investigate how much of the HF risk reduction could be explained by the actual net changes in such components induced by high dose statin treatment as compared to usual dose. We also wanted to compare the predictive value of lipoprotein components with those of established risk factors such as diabetes and hypertension.