Elsevier

The Lancet HIV

Volume 2, Issue 2, February 2015, Pages e52-e63
The Lancet HIV

Articles
Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S2352-3018(14)00032-0Get rights and content

Summary

Background

HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population.

Methods

In a randomised, double-blind, placebo-controlled trial, 40 HIV-infected participants with subclinical coronary atherosclerosis, evidence of arterial inflammation in the aorta by fluorodeoxyglucose (FDG)-PET, and LDL-cholesterol concentration of less than 3·37 mmol/L (130 mg/dL) were randomly assigned (1:1) to 1 year of treatment with atorvastatin or placebo. Randomisation was by the Massachusetts General Hospital (MGH) Clinical Research Pharmacy with a permuted-block algorithm, stratified by sex with a fixed block size of four. Study codes were available only to the MGH Research Pharmacy and not to study investigators or participants. The prespecified primary endpoint was arterial inflammation as assessed by FDG-PET of the aorta. Additional prespecified endpoints were non-calcified and calcified plaque measures and high risk plaque features assessed with coronary CT angiography and biochemical measures. Analysis was done by intention to treat with all available data and without imputation for missing data. The trial is registered with ClinicalTrials.gov, number NCT00965185.

Findings

The study was done from Nov 13, 2009, to Jan 13, 2014. 19 patients were assigned to atorvastatin and 21 to placebo. 37 (93%) of 40 participants completed the study, with equivalent discontinuation rates in both groups. Baseline characteristics were similar between groups. After 12 months, change in FDG-PET uptake of the most diseased segment of the aorta was not different between atorvastatin and placebo, but technically adequate results comparing longitudinal changes in identical regions could be assessed in only 21 patients (atorvastatin Δ −0·03, 95% CI −0·17 to 0·12, vs placebo Δ −0·06, −0·25 to 0·13; p=0·77). Change in plaque could be assessed in all 37 people completing the study. Atorvastatin reduced non-calcified coronary plaque volume relative to placebo: median change −19·4% (IQR −39·2 to 9·3) versus 20·4% (−7·1 to 94·4; p=0·009, n=37). The number of high-risk plaques was significantly reduced in the atorvastatin group compared with the placebo group: change in number of low attenuation plaques −0·2 (95% CI −0·6 to 0·2) versus 0·4 (0·0, 0·7; p=0·03; n=37); and change in number of positively remodelled plaques −0·2 (−0·4 to 0·1) versus 0·4 (−0·1 to 0·8; p=0·04; n=37). Direct LDL-cholesterol (−1·00 mmol/L, 95% CI −1·38 to 0·61 vs 0·30 mmol/L, 0·04 to 0·55, p<0·0001) and lipoprotein-associated phospholipase A2 (−52·2 ng/mL, 95% CI −70·4 to −34·0, vs −13·3 ng/mL, −32·8 to 6·2; p=0·005; n=37) decreased significantly with atorvastatin relative to placebo. Statin therapy was well tolerated, with a low incidence of clinical adverse events.

Interpretation

No significant effects of statin therapy on arterial inflammation of the aorta were seen as measured by FDG-PET. However, statin therapy reduced non-calcified plaque volume and high-risk coronary plaque features in HIV-infected patients. Further studies should assess whether reduction in high-risk coronary artery disease translates into effective prevention of cardiovascular events in this at-risk population.

Funding

National Institutes of Health, Harvard Clinical and Translational Science Center, National Center for Research Resources.

Introduction

Coronary artery disease is a major cause of morbidity and mortality for patients living with long-term HIV infection.1, 2, 3, 4 Epidemiological studies fully adjusting for numerous risk factors and investigating validated cardiovascular events show increased risk in patients with HIV compared with that in those without.5 Efficacious cardiovascular risk reduction interventions for HIV-infected patients are urgently needed.

Several studies have shown increased prevalence of subclinical atherosclerosis, including a predominant increase in non-calcified plaque in HIV-infected patients compared with patients without HIV, controlling for traditional coronary artery disease risk factors.6, 7, 8 Additional studies in HIV-infected patients have shown evidence of arterial inflammation9 and increased vulnerable plaque morphology on coronary CT angiography (CCTA).10 Greater volumes of non-calcified plaque and vulnerable plaque morphology on CCTA are associated with future major adverse cardiac events.11

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce the numbers of cardiac events and mortality in the general population. Imaging trials in patients without HIV have also shown that intensive statin therapy can slow progression of coronary atherosclerosis and even result in disease regression.12, 13, 14 Previous studies of statin therapy in HIV-infected patients have shown improvement in lipid concentrations and reduction in markers of inflammation, as well as improvement in endothelial function, but no studies have prospectively investigated the effects of statins on direct measurements of arterial inflammation and coronary atherosclerosis in this population of patients.15, 16, 17, 18 We did a randomised, double-blind, placebo-controlled trial to investigate the effects of a statin on arterial inflammation and coronary atherosclerosis in HIV-infected people without known cardiovascular disease or raised LDL cholesterol concentrations but with subclinical atherosclerosis and arterial inflammation.

We hypothesised that coronary atherosclerosis would progress at a rapid rate in this population of HIV-infected people, despite normal concentrations of baseline LDL-cholesterol, and that treatment with a statin would reduce arterial inflammation, deter the progression of coronary atherosclerosis, and reduce non-calcified plaque volume and vulnerable plaque morphology, resulting in a decrease in high-risk atherosclerotic lesions.

Section snippets

Study design and participants

This study was a single-site, randomised, double-blind, placebo-controlled clinical trial. Study participants were men and women with HIV disease, no history of cardiovascular disease or cardiac symptoms, and evidence of subclinical coronary atherosclerosis, defined by presence of one or more plaques on CCTA but without clinically significant stenosis, defined as greater than 50% left main stenosis or greater than 70% stenosis in any major vessel. Additionally, participants who showed plaque on

Results

The study ran from Nov 13, 2009, to Jan 13, 2014. We screened 81 HIV-infected patients; screening was sequential such that the presence of plaque was first established by CCTA (figure 1). The study took several years to complete because treatment duration was 1 year and recruitment was at a single site. 40 participants were randomly assigned to receive either atorvastatin (n=19) or placebo (n=21). Age, sex, race and ethnicity, body-mass index, and Framingham 10 year risk estimate were similar

Discussion

In this randomised, double-blind, placebo-controlled study of HIV-infected patients with subclinical atherosclerosis, atorvastatin did not seem to reduce arterial inflammation in the aorta, but treatment deterred overall coronary plaque progression and induced coronary plaque regression in HIV-infected patients, largely through effects on non-calcified plaque volume. Atorvastatin reduced coronary non-calcified plaque volume by 19·4% in 1 year in the patients in our study, compared with an

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