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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
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January 08, 2015
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Now, we show that statin therapy can reduce the number of plaques with these vulnerability features in patients with HIV as well as the volume of non-calcified plaque.
We did not see a statistically significant relation of change in LDL to plaque, suggesting other mechanisms might also be operative to achieve these results.
The rapid progression and nature of coronary plaque in patients randomly assigned to placebo provide evidence regarding the natural history of atherosclerosis in HIV. Not only did plaque volume increase, but three of 20 patients in the placebo group had progression of clinically significant coronary stenosis after 1 year follow-up. By contrast, none of the statin-treated group progressed to clinically significant stenosis. Evidence for increased atherosclerotic disease progression in HIV-infected patients suggests the need for more aggressive treatment with statins as in other high-risk populations.
Our study is the first to investigate the effects of a statin on coronary atherosclerosis in patients with HIV (panel). In the non-HIV-infected population, statins at high doses can induce regression of atheroma volume measured by intravascular ultrasound 13, 14 in patients with known coronary disease. In the current study, we investigated rates of plaque regression over 1 year in HIV-infected patients with subclinical plaque using CCTA and showed a 1 year plaque regression rate of 64⋅7% with atorvastatin up to 40 mg a day.
Previous studies with CCTA to assess treatment effects of statins in the general population were not randomised trials, but also shed light on the potential effects of statins on atherosclerotic lesions. In a retrospective observational study46 in non-HIV patients, statin therapy reduced the progression of low attenuation plaque and non-calcified plaque measured by CCTA. In another non-randomised study of patients without HIV, fluvastatin reduced low attenuation plaque volume on serial cardiac CTA assessment, similar to what we found in HIV-infected patients. 47 Therefore non-randomised studies in non-HIV infected patients suggest a potential effect of statins on non-calcified plaque. The current study is the first randomised placebo-controlled trial to show an effect of statins on non-calcified plaque and plaque regression in any population by CCTA.
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 increase of 20⋅4% in the placebo group. Atorvastatin reduced high-risk plaque features such as low attenuation and positive remodelling, which have been linked to acute coronary events.39
These changes occurred in the context of a net change in LDL cholesterol concentration of 1⋅30 mmol/L (1⋅00 mmol/L reduction in atorvastatin group and 0⋅30 mmol/L increase in placebo group) in a group in whom baseline LDL cholesterol was not raised by design (eg, ≤3⋅37 mmol/L or 130 mg/dL). The study population, on ART, without a clinical history of cardiovascular disease, but with subclinical plaque and arterial inflammation is representative of patients with HIV at risk for coronary artery disease. The VACS score in our population was comparable to that seen in other HIV populations including those described in the ART Cohort Collaboration.35
One objective of this study was to assess the effects of statins on specific inflammatory endpoints. Previous studies of statin therapy measured biomarkers of inflammation, immune activation, and endothelial function in HIV-infected patients but have not assessed direct measures of arterial inflammation. A significant reduction of CRP was not seen in a recent study of rosuvastatin in HIV-infected patients.
We recorded a small reduction in log CRP concentration with atorvastatin at 40 mg/day, the effect was not significant. We did record a significant reduction in Lp-PLA2 by 18⋅3%, consistent with findings from another study. Lp-PLA2 is an inflammatory enzyme secreted by monocytes, macrophages, and other inflammatory cells that hydrolyses phospholipids on lipoproteins including oxidised LDL particles within the arterial intima, and leads to recruitment of monocytes to the intima. Concentrations of Lp-PLA2 and its activity are predictive of cardiovascular events in many large epidemiological cohorts; however, darapladib, a selective oral inhibitor of Lp-PLA2, did not reduce cardiovascular events in a study of non HIV-infected patients.
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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
January 08, 2015
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.
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.
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.
Additional studies in HIV-infected patients have shown evidence of arterial inflammation and increased vulnerable plaque morphology on coronary CT angiography (CCTA). Greater volumes of non-calcified plaque and vulnerable plaque morphology on CCTA are associated with future major adverse cardiac events.
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. 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. 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.
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 between both groups at baseline (table 1). Prevalence of hypertension, diabetes mellitus, and current smoking were similar between groups as were blood pressure, fasting glucose, HbA1c, total cholesterol, HDL, LDL, and CRP measurements. HIV disease variables, including duration and type of ART, were also similar in the two groups. Participants were all on ART and most patients had undetectable viraemia with similar immunological and virological indices between groups (table 1). Four patients in the placebo group and three in the atorvastatin group had detectable viraemia but the maximum viral load at baseline was 355 copies per mL and all but three had viral loads less than 100 copies per mL. Patients were all on ART for a mean of 11–12 years without differences between the groups. All patients had started ART more than 2 years before the study and all were on a stable regime for at least 6 months before study initiation. Baseline VACS scores were not different between the atorvastatin and placebo groups (appendix p 1). Viral-load information was given to referring physicians responsible for ongoing clinical care of patients. At baseline, no significant differences were noted between groups in arterial inflammation, plaque volume, or other atherosclerosis variables (table 2).
Atorvastatin decreased non-calcified coronary plaque volume as compared with placebo over 12 months (figure 2, table 2; p=0⋅03). On a percentage basis, patients receiving atorvastatin had a decrease in plaque volume compared with an increase in non-calcified plaque volume in the placebo group (table 2; p=0⋅009). Additionally, atorvastatin reduced total coronary plaque volume compared with placebo (p=0⋅02); patients taking atorvastatin had a decrease in total plaque volume, which increased over 12 months in those taking placebo (p=0⋅01).
The number of segments with low attenuation plaques (<40 HU) and number of positively remodelled plaques (remodelling index >1⋅05) were significantly reduced by atorvastatin compared with placebo (p=0⋅03 and 0⋅04, respectively, table 2). Change in number of plaques with spotty calcifications was not significantly different between the two groups (table 2).
11 (64⋅7%) of 17 patients in the atorvastatin group had regression of coronary atherosclerosis (based on any reduction in plaque volume) compared with four (20%) of 20 in the placebo group (p=0⋅008). Conversely, 16 patients (80%) in the placebo group had progression of coronary atherosclerosis (based on any increase in plaque volume) compared with six patients (35⋅3%) patients in the atorvastatin group (table 2). No obvious effect of sex on plaque regression or progression was seen by Breslow Day test (p=0⋅17). Figure 3 shows an example of progression of coronary plaque in the proximal left anterior descending coronary artery of an HIV-infected participant randomly assigned to receive placebo.
Three participants in the placebo group developed clinically significant increases in the extent of stenosis (two participants in the placebo group had stenosis that progressed to beyond 70% at 12 months and one participant in the placebo group developed >50% stenosis at 12 months). Although of clinical relevance, the difference between groups was not statistically significant. None of these patients developed symptoms of coronary artery disease. By contrast, no participants in the atorvastatin group developed clinically significant increases in extent of stenosis (table 2).
In a supplementary analysis, the effect of atorvastatin on plaque segments was analysed. Number of segments with plaque and number of segments with non-calcified plaque both decreased in the group assigned to atorvastatin compared with those assigned placebo, but segments with calcified plaque or mixed plaque did not change between the groups (appendix p 3).
No significant differences were noted in coronary artery calcium score, calcium mass, calcium volume or calcium density at baseline or the change over time between the two groups (table 2).
Total cholesterol and direct LDL significantly decreased with atorvastatin compared with placebo: total cholesterol change -1⋅23 mmol/L (95% CI -1⋅53 to -0⋅93) versus 0⋅12 mmol/L (-0⋅12 to 0⋅37; p<0⋅0001); direct LDL change -1⋅00 mmol/L (-1⋅38 to 0⋅61) versus 0⋅30 mmol/L (0⋅04 to 0⋅55; p<0⋅0001; table 3; figure 4). There was no statistically significant relation between change in LDL and plaque (appendix p 5). No statistically significant differences in changes in fasting glucose or HbA1c were detected between the two groups (table 3).
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