Randomized Placebo-Controlled Trial Assessing the Effect of 24-Week Fenofibrate Therapy on Circulating Markers of Abdominal Aortic Aneurysm: Outcomes From the FAME -2 Trial

Abstract

Background There is no drug therapy for abdominal aortic aneurysm ( AAA ). FAME-2 (Fenofibrate in the Management of Abdominal Aortic Aneurysm 2) was a placebo-controlled randomized trial designed to assess whether administration of 145 mg of fenofibrate/d for 24 weeks favorably modified circulating markers of AAA. Methods and Results Patients with AAA s measuring 35 to 49 mm and no contraindication were randomized to fenofibrate or identical placebo. The primary outcome measures were the differences in serum osteopontin and kallistatin concentrations between groups. Secondary analyses compared changes in the circulating concentration of AAA -associated proteins, and AAA growth, between groups using multivariable linear mixed-effects modeling. A total of 140 patients were randomized to receive fenofibrate (n=70) or placebo (n=70). By the end of the study 3 (2.1%) patients were lost to follow-up and 18 (12.9%) patients had ceased trial medication. A total of 85% of randomized patients took ≥80% of allocated tablets and were deemed to have complied with the medication regimen. Patients' allocated fenofibrate had expected reductions in serum triglycerides and estimated glomerular filtration rate, and increases in serum homocysteine. No differences in serum osteopontin, kallistatin, or AAA growth were observed between groups. Conclusions Administering 145 mg/d of fenofibrate for 24 weeks did not significantly reduce serum concentrations of osteopontin and kallistatin concentrations, or rates of AAA growth in this trial. The findings do not support the likely benefit of fenofibrate as a treatment for patients with small AAA s. Clinical Trial Registration URL : www.anzctr.org.au . Unique identifier: ACTRN 12613001039774.

Keywords: Fenofibrate; abdominal aortic aneurysm; biomarkers; clinical trial.

Figure 1

Consolidated Standards of Reporting Trials diagram showing the flow of patients for the current trial. SAE indicates serious adverse event.

Figure 2

Serum triglyceride (A), estimated glomerular filtration rate (eGFR, B), and circulating homocysteine concentrations (C) in patients allocated fenofibrate (red circles) or placebo (blue squares) at recruitment, and after 3 and 24 weeks. Numbers of participants assessed at each time point for each marker are shown in the respective tables. P values refer to the interaction between time and drug allocation for the follow‐up period as determined using unadjusted linear mixed effects (LME) analysis. ^‡Natural log‐transformed data assessed in LME. *Significant differences between groups for that time point as assessed by LME.

Figure 3

Circulating concentrations of osteopontin (OPN A), kallistatin (B), resistin (C), osteoprotegerin (OPG D), matrix metalloproteinase‐9 (MMP‐9 E), and D‐dimer (F) in patients allocated fenofibrate (red circles) or placebo (blue squares) at recruitment, and after 3 and 24 weeks. The number of patients included at each time point for the markers is detailed in (G) (*D‐dimer was assessed for 66 patients in the placebo group at 24 weeks). P values refer to the interaction between time and drug allocation for the follow‐up period as determined using unadjusted linear mixed effects (LME) analysis. ^‡Natural log‐transformed data assessed in LME. ^αReported P value refers to analysis of data normalized to baseline levels to account for observed differences between groups at recruitment.

Figure 4

Serum concentrations of total cholesterol (A), high‐density lipoprotein cholesterol (HDL‐C, B), low‐density lipoprotein cholesterol (LDL‐C, C), and very low‐density lipoprotein cholesterol (VLDL‐C, D) in patients allocated fenofibrate (red circles) or placebo (blue squares) at recruitment, and after 3 and 24 weeks. The number of patients included at each time point is detailed in the corresponding tables. P values refer to the interaction between time and drug allocation for the follow‐up period as determined using unadjusted linear mixed effects analysis. All data were natural log‐transformed for analysis. ^αReported P value refers to analysis of data normalized to baseline levels to account for observed differences between groups at recruitment.

Figure 5

AAA (abdominal aortic aneurysm) growth in participants allocated fenofibrate (red circles) or placebo (blue squares) over 24 weeks. AAA diameters were read by 2 observers and assessed by measuring from inner wall to inner wall (ITI, A and D), leading edge to leading edge (LELE, B and E), and outer wall to outer wall (OTO, C and F). Baseline data were available for all recruited patients; however, 3 participants in the placebo group did not undergo imaging at 24 weeks because of study withdrawal or death (n=67 at for the placebo group at 24 weeks). P values relate to the interaction between time and treatment allocation as assessed by unadjusted linear mixed effects analysis.