ArticlesEffect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP): a prospective, randomised, double-blind trial
Introduction
High concentrations of LDL-cholesterol are a risk factor for atherosclerotic vascular disease. Clinical sequelae, however, are preceded by silent changes. B-mode ultrasound allows such atherosclerotic changes in the walls of the carotid and femoral arteries to be seen, and it has been widely endorsed and standardised for measurement of intima media thickness (IMT).1 Cross-sectional studies indicate an association between carotid IMT and cardiovascular risk factors,2, 3 and the prevalence of cardiovascular disease.4, 5 More importantly, in prospective studies6, 7 carotid IMT was able to predict coronary artery disease (CAD). Consequently, assessment of carotid IMT changes over time has become important in clinical intervention trials.8, 9, 10
Patients with heterozygous familial hypercholesterolaemia are at an increased risk of premature CAD. This disorder provides the framework for the relation between LDL and atherogenesis and it is frequently used as a model for lipid-lowering interventions. Results of several small studies show that carotid IMT is greatly increased in these patients.3, 9, 11
In heterozygous adults with familial hypercholesterolaemia, life-long treatment with lipid lowering drugs is indicated, because these drugs slow down progression of the disease, as judged by coronary angiography.12 Patient tolerance and acceptance of the combination of drugs needed to successfully lower LDL concentrations, however, is poor.13 The treatment of choice is statin, an HMG-CoA-reductase inhibitor.
In most hypercholesterolaemic patients, simvastatin can reduce LDL-cholesterol concentrations by 30–40%.9, 14, 15 Atorvastatin is an inhibitor of HMG-CoA reductase, which can lower LDL-cholesterol in patients with primary hyperlipidaemia by as much as 61% over the 10–80 mg dose range.16 We postulated that a large reduction in LDL-cholesterol would slow disease progression in heterozygous patients. Our aim was to determine whether aggressive LDL-cholesterol lowering with atorvastatin 80 mg, would slow atherosclerosis progression, as measured by carotid IMT.
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Patients
The study design and baseline characteristics of the patients have been described elsewhere.17 Briefly, between 1997 and 1998, men and women aged 30–70 years with familial hypercholesterolaemia were screened for eligibility. Patients were either previously untreated or treated but with LDL-cholesterol concentrations remaining above 4·5 mmol/L. After an 8 week placebo run-in, in which all lipid-lowering drugs were discontinued, baseline measurements of lipoprotein variables and IMT were
Results
45 of the 325 patients of the intent-to-treat population did not complete the study (14%) (figure 1) because of: a wish to become pregnant (two in simvastatin group), raised transaminases (one in each group), menorraghia (one in simvastatin group), emotional distress (two in simvastatin, three in atorvastatin group), muscle ache (two in each group), insufficient response to treatment (seven in the simvastatin and one in the atorvastatin group), death (three, two due to cardiac disease [one in
Discussion
Our data support the hypothesis that aggressive LDL-cholesterol lowering of at least 45% is warranted to modify IMT progression into regression. The primary efficacy endpoint—mean 2-year change in carotid IMT—showed significant regression in the atorvastatin group, whereas the IMT in the simvastatin group increased. We recorded a treatment effect by baseline IMT in patients with higher baseline IMT values responding better to atorvastatin than did patients with low baseline values. In previous
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2021, Trends in Cardiovascular MedicineCitation Excerpt :However, carotid ultrasound markers describing atherosclerotic plaques (i.e., plaque number, plaque score and percent area stenosis) have been reported to be more sensitive than the c-IMT for CVD risk prediction in FH patients [107]. Among these markers, the carotid plaque score (the sum of the maximal thickness of atherosclerotic plaques on both near wall and far wall in the bilateral common and internal carotid arteries) was shown to predict coronary artery disease in FH patients [108,109]. In several studies, the CT-based evaluation of coronary artery calcium (CAC) with the Agatston score, identifying the presence or absence of coronary calcific atherosclerotic lesions, was reported as a reliable modality to predict the risk of future CVD events in the general population.