Aggressive Lipid Lowering In Patients With Coronary Heart Disease

Ronald Karnik, MD

2nd Department of Medicine, Krankenanstalt Rudolfstiftung, Vienna, Austria

Abstract

Atherosclerosis is by far the most frequent cause of coronary heart disease (CHD). Large studies have provided unequivocal evidence that lipid lowering by statins significantly reduce the incidence of CHD endpoints. New insights in the pathophysiology show that statin therapy reduces progression of atherosclerosis, and leads to plaque stabilization as well as a reduced plaque thrombogenicity. In patients with CHD, treatment with statins may prevent plaque rupture of atherosclerotic lesions and therefore reduces the occurrence of acute coronary syndromes. Patients with hemodynamically relevant stenosis and angina interfering with quality of life and patients who have less exercise tolerance may be regarded as candidates for coronary intervention. In these patients, aggressive lipid-lowering may complement angioplasty by stabilizing untreated lesions.

According to the guidelines of the National Cholesterol Educational Program, LDL-cholesterol of no more than 100mg/dl is considered optimal in patients with CHD or other atherosclerotic diseases.

(Heart Views. 2001;2(1):16-19) © 2001 Hamad Medical Corporation.

Keywords: ® atherosclerosis ® lipids ® statins ® acute coronary syndrome

Introduction

Atherosclerosis is by far the most frequent cause of coronary heart disease (CHD). Epidemiologic, clinical, genetic and experimental studies have clearly proven that high serum levels of cholesterol are related causally to atherosclerosis and increased risk of CHD1.

In recent years, new insights in plaque morphology have been obtained and since then, we have entered a new era in the biology of acute coronary syndromes.

Randomized placebo-controlled megastudies – 4S (simvastatin), CARE, WOSCOP, LIPID (pravastatin), AFCAPS/TexCAPS (lovastatin)2-6 have provided unequivocal evidence that lipid lowering by statins significantly reduces the incidence of CHD endpoints.

1. How does lipid-lowering improve patients' outcome?

1.1. Regression of fixed stenosis by lipid-lowering therapy

Until the late 1970s it was advocated that human atherosclerosis is irreversible. In the 1980s several large intervention trials with diet and various drug therapies were completed and clearly demonstrated regression of coronary lesions. Major studies7-9 using coronary angiography have shown that intensive lipid modification by a variety of interventions retards the progression of atherosclerotic lesions, and in a subset of patients, lead to their regression. However, the clinical benefit of lipid lowering in terms of event reduction by far outweights the angiographic improvement, which is modest and rather disappointing. In order to solve this paradox, we have to focus on plaque composition and vulnerability to rupture and plaque thrombogenicity, rather than on plaque size and stenosis severity.

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1.2. The vulnerable plaque concept and the role of inflammation

Most acute coronary syndromes are caused by plaque rupture and superimposed thrombosis. An unstable plaque is a lipid-rich, friable plaque, which is ready to rupture. The major determinants for plaque rupture are shown in Table 1. Accumulation

of lipids in the plaque with an inadequate fibrotic response and high concentrations of leucocytes result in plaque vulnerability and instability. Monocytes and macrophages show a high biochemical activity by releasing metalloproteinases and tissue factor. These substances may contribute to the rupture of the plaque as well as to the formation of the final clot. There is increasing evidence that inflammation plays an important role in both the pathogenesis of atherosclerosis and subsequent plaque instability. Acute exacerbation of inflammation maybe associated with acute coronary syndromes such as myocardial infarction and unstable angina. Acute phase proteins like C-reactive protein have been documented in a number of studies to correlate with the risk for development of coronary artery disease10, as well as to predict the risk of acute events in patients with CHD.11

In the CARE study, Ridkers16 demonstrated that statin therapy significantly reduced levels of CRP over the period of the trial. Subjects with elevated levels of CRP at baseline and randomized to placebo had increased CRP over time. The evidence of inflammation after myocardial infarction is associated with increased risk of recurrent coronary events. Statin therapy may decrease this risk, an observation consistent with a non-lipid effect of these agents.

1.3. Thrombogenicity of plaques

An unstable lipid-rich plaque contains a high density of monocytes and macrophages, which are chemically very active.17 If the plaque ruptures, substances such as tissue factor, a coagulant factor, are released, which may lead to clot formation.18 However, in about 30% of acute coronary syndromes, thrombus formation occurs without plaque rupture. Stenotic plaques without endothelium may be in a hypercoagulative state activated by hyperlipidemia, cigarette smoking and diabetes19 (Table 3). Activation of monocytes and macrophages leads to the release of tissue factor, which produces thrombin and platelet activation. In this hypercoagulative state, a simple fissure in the plaque or a de-endothelialized plaque surface may trigger thrombus formation on the surface of the plaque.

In a number of experimental and clinical studies20, statin therapy was associated with a significant reduction of tissue factor, an important membrane particle, which has been correlated to acute coronary syndromes.

2. The role of statin therapy in patients with CHD

2.1. Statins versus angioplasty

The AVERT study,21 showed that high-dose atorvastatin was at least as effective as angioplasty in reducing coronary events in patients with stable angina. For most patients, lipid-lowering drug therapy and percutaneous coronary interventions are not alternative treatment regimens but complementary.

Statins may prevent plaque rupture of hemodynamically unimportant atherosclerotic lesions and reduce occurrence of new acute coronary syndromes due to plaque stabilization and reduction of thrombogenicity of vulnerable plaques. However, plaque regression only occurs in the dimension of a tenth of a millimeter and therefore cannot be seen as an important factor to improve symptoms in patients with severely stenosed coronary arteries. Patients with hemodynamically significant stenosis and angina, which interferes with quality of life, and patients with decreased exercise tolerance, may be regarded as candidates for coronary intervention. In these patients, aggressive lipid lowering may complement angioplasty by stabilizing untreated lesions.

2.2. Should all patients with CHD be treated with statins?

According to the guidelines of the National Cholesterol Educational Program (NCEP)23 LDL-cholesterol of no more than 100mg/dl is considered optimal in patients with CHD or other atherosclerotic diseases. The NCEP-algorithm for lipid-lowering based on LDL-cholesterol levels is depicted in Table 4. Patients with established CHD are candidates for lipid-lowering drug therapy when LDL-cholesterol is 130 mg/dl or higher. In CHD patients with LDL-cholesterol levels 100-129mg/dl, the physician should exercise clinical judgment in deciding whether to initiate drug treatment. The American College of Cardiology/AHA Task Force on Practice Guidelines24 has recommended beginning lipid-lowering drug therapy as early as the time of discharge from the hospital in such patients.

However, the greatest and continuing challenge for all physicians and health care providers will consist in educational tasks. If we are able to provide a clear message concerning target levels of LDL-cholesterol to the general population and achieve a high acceptance rate, then changes in life style in combination with an aggressive lipid-lowering drug therapy may contribute to reduce morbidity and mortality of cardiovascular diseases.