2015 - A Secondary Analysis of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Study Shows That Atorvastatin Therapy Reduces Progression of Carotid Intima Medial Thickening in Pubertal SLE Patients with Higher C Reactive Protein

Tuesday, November 8, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Stacy P. Ardoin1, Laura E. Schanberg2, Christy I. Sandborg3, Huiman Barnhart4, Eric Yow4, Greg Evans5, Kelly Mieszkalski2, Norman T. Ilowite6, Emily von Scheven7, B. Anne Eberhard8, Lisa F. Imundo9, Deborah M. Levy10, Yuki Kimura11, Earl D. Silverman12, Suzanne L. Bowyer13, Marilynn G. Punaro14, Nora G. Singer15, David D. Sherry16, Deborah K. McCurdy17, Marisa Klein-Gitelman18, Carol A. Wallace19, Richard M. Silver20, Linda Wagner-Weiner21, Gloria Higgins22 and Hermine Brunner23, 1Ohio State University, Columbus, OH, 2Duke University Medical Center, Durham, NC, 3Stanford University, Palo Alto, CA, 4Duke Clinical Research Institute, Durham, NC, 5Winston-Salem, NC, 6Children's Hospital Montefiore, Bronx, NY, 7UC San Francisco, San Francisco, CA, 8Cohen Children's Hospital Medical Center, New Hyde Park, NY, 9Childrens Hospital of New York, Columbia University Medical Center, New York, NY, 10The Hospital for Sick Children, Toronto, ON, 11Pediatrics, Hackensack, NJ, 12Hospital for Sick Children, Toronto, ON, 13James Whitcomb Riley Hospital, Indianapolis, IN, 14Texas Scottish Rite Hospital, Dallas, TX, 15Director, Division of Rheumatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, OH, 16Children's Hospital of Philadelphia, Philadelphia, PA, 17Mattel Children's Hospital, University of California, Los Angeles, Los Angeles, CA, 18Children's Memorial Hospital, Chicago, IL, 19Childrens Hosp & Regional Med, Seattle, WA, 20MUSC, Charleston, SC, 21University of Chicago Hospital, Chicago, IL, 22NATIONWIDE CHILDRENS HOSPITAL, Columbus, OH, 23Cincinnati Children's Hospital Medical Center, Cincinnati, OH
Presentation Number: 2015

Background/Purpose: APPLE assessed atorvastatin's efficacy in reducing carotid intimal medial thickening (CIMT) progression in pediatric SLE (pSLE).  While the primary endpoint of reduced mean-mean common CIMT progression was not met, observed trends of near significance in several CIMT segments suggested atorvastatin may reduce CIMT progression. Secondary analyses were performed to determine whether treatment effect was consistent across subgroups defined by LDL, high-sensitivity c-reactive protein (hscrp), age, pubertal status, SLE duration and medication adherence.

Method: APPLE is a randomized, placebo-controlled, multicenter trial randomizing 221 subjects with pSLE (age 10-21 years) to 36 months of atorvastatin or placebo. CIMT was measured by standard protocol at 0, 12, 24 and 36 months. Fasting lipids and hscrp were measured centrally. Subgroups were defined as LDL < or >/= 110 mg/dL, hscrp < or >/= 1.5 mg/dL, age < or >/= 15.5 yrs, SLE duration < or ³ 24 months, adherence < or >/= 75%. Prepubertal status was defined by self-reported Tanner stage < 4. An additional combined subgroup of post-pubertal subjects with hscrp ³ 1.5 mg/dL vs. others was defined. 

The statistical approach replicated primary APPLE efficacy analysis comparing CIMT progression rates between treatment groups based on test of interaction between treatment group and time in a longitudinal linear mixed effects model. Similar models were used to assess non-CIMT outcomes. Indicator variables were included for subgroup level as well as two- and three-way interactions between subgroup, treatment group and time between subgroup level, treatment group and time. All statistical analyses were 2-sided, and the level of significance for all analyses was 0.05.  

Result:  Differences in treatment effects between hscrp subgroups were identified for mean-mean common (p=0.029) and mean-mean near wall (p=0.014).  In both cases, the reduction in CIMT progression associated with atorvastatin assignment was more pronounced in the elevated hscrp subgroup.  Similar differences were identified by pubertal status for mean-mean bifurcation (p=0.019) mean-max near wall (p=0.027) and mean-mean near wall (p=0.021), and by adherence for mean-mean far wall (p=0.035) and mean-mean near wall (p=0.028), where reduction in CIMT progression with atorvastatin assignment was more pronounced among post-pubertal or more adherent participants.  No significant differences in treatment effects were observed between subgroups defined by LDL, age or SLE duration. The combined pubertal and high hscrp subgroup  atorvastatin group had lower CIMT progression rates in five of 12 CIMT segments:  mean-mean common (p=0.005), mean-mean (p=0.008), mean-mean bifurcation (p=0.023), mean-max near wall (p=0.029), and mean-mean near wall (p=0.002). 

Conclusion:  These exploratory results need to be confirmed and interpreted cautiously  as multiple comparisons were performed. APPLE secondary analyses  showed a trend of lower CIMT progression rates in the atorvastatin-treated pubertal and elevated hscrp subgroups, particularly in the combined pubertal subjects with high hscrp, suggesting that this subgroup may benefit from statin therapy.  


Keywords: cardiovascular disease, pediatric rheumatology, prevention, statins and systemic lupus erythematosus (SLE)

Disclosure: S. P. Ardoin, None; L. E. Schanberg, Pfizer Inc, 9 ; C. I. Sandborg, None; H. Barnhart, None; E. Yow, None; G. Evans, None; K. Mieszkalski, None; N. T. Ilowite, Abbott Immunology Pharmaceuticals, 8, Genentech and Biogen IDEC Inc., 8, Regeneron, 2, Novartis Pharmaceutical Corporation, 5, Centocor, Inc., 5 ; E. von Scheven, None; B. A. Eberhard, None; L. F. Imundo, None; D. M. Levy, None; Y. Kimura, None; E. D. Silverman, None; S. L. Bowyer, None; M. G. Punaro, None; N. G. Singer, None; D. D. Sherry, None; D. K. McCurdy, None; M. Klein-Gitelman, None; C. A. Wallace, Amgen,Pfier, Centocor, Novartis, BMS, 2 ; R. M. Silver, None; L. Wagner-Weiner, None; G. Higgins, None; H. Brunner, None.