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

Abstract

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.

Conflict of interest statement

Declaration of Interests

Dr. Grinspoon has consulted with Navidea, AstraZeneca, NovoNordisk, and Theratechnologies, and received grant support from Gilead, Amgen, KOWA Pharmaceuticals, and Theratechnologies, unrelated to this manuscript. Dr. Robbins has received grant support from Gilead Sciences unrelated to this manuscript. Dr. Hoffmann received grant support from Siemens Healthcare, American College of Radiology Imaging Network, and HeartFlow Inc., unrelated to this manuscript. Dr. Tawakol has received grant support from Genentech/Roche, BMS, Takeda, GSK, and VBL and personal fees from Novartis, Genentech/Roche, BMS, Cerenis, Takeda, Actelion, GSK, and Amgen unrelated to this manuscript. All authors report no conflicts of interest.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Consort Diagram -- Flow of Participants

Figure 2. Comparison of the 1-Year Change in Noncalcified Plaque Volume in HIV Patients Randomized to Atorvastatin vs. Placebo

Horizontal line in center of box denotes median and top of box denotes 75th centile and lower end of box denotes 25th centile.

Figure 3. Increasing Noncalcified Plaque in proximal left anterior descending (LAD) coronary artery in a Patient on Placebo

Progressive coronary plaque in the proximal left anterior descending coronary artery (LAD, arrow) on A) initial and B) 12-month follow-up CCTA in a 58-year-old woman with HIV. Plaque volume increased from 11 to 124 mm3 (arrow). High risk morphology (HRM) features including positive remodeling and low density lipid core developed on follow-up. This participant was randomized to placebo during the study.

Figure 4. Comparison of the 1-Year Change in Direct LDL in HIV Patients Randomized to Atorvastatin vs. Placebo

Bars represent means and error bars represent standard deviations.