Statins Not Routinely Indicated for Children and Adolescents with Lupus
Embargo expired: 11/7/2010 5:00 PM EST
Source Newsroom: American College of Rheumatology (ACR)
Newswise — While statins are known to help prevent the progression of atherosclerosis, research presented this week at the American College of Rheumatology Annual Scientific Meeting in Atlanta indicates they should not be routinely prescribed in children and adolescents with lupus despite their increased risk of premature atherosclerosis.
Lupus, or SLE, is a chronic inflammatory disease that can affect the skin, joints, kidneys, lungs, nervous system, and other organs of the body. Usually, patients have skin rashes and arthritis, as well as fatigue and fever. It is often more severe when it begins in childhood. Lupus has been identified as a strong independent risk factor for heart attack and stroke, and children with lupus are at a particularly high risk because of their lifelong exposure to the disease. Atherosclerosis—a buildup of fatty deposits in the artery walls—which normally leads to heart attack and strokes in older adults, starts at an at an unusually early age and progresses more quickly in people with lupus.
Statins have been shown to reduce cardiovascular complications and death among the general adult population, but they have not been studied in the prevention of atherosclerosis among young people with lupus. In the largest trial of its kind—and the first major trial completed by the Childhood Arthritis and Rheumatology Research Alliance (called CARRA)—researchers recently completed a study looking at whether the use of statins would be helpful enough in the prevention of atherosclerosis in children and adolescents with lupus to make it worthwhile for them to start taking at such a young age.
With funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health, researchers followed 221 participants (ages 10 to 21) with lupus who were recruited through 21 CARRA sites. The participants were randomly placed into two groups: one received atorvastatin (Lipitor®) and one received placebo for 36 months. Participants also received hydroxychloroquine, aspirin, a daily multi-vitamin, as well as recommendations for a low cholesterol diet and cardiovascular risk factor counseling. All participants continued routine care for lupus as prescribed by their local pediatric rheumatologist.
The researchers used a very accurate ultrasound technique that can detect even tiny differences in the thickening of the arterial wall of the carotid arteries, which has been shown to predict future heart attacks and strokes.
They also studied blood lipid levels, blood markers of inflammation, lupus disease activity and damage as well as each participant’s quality of life.
The study showed no clinically important differences in measurements of the carotid artery thickening for those participants taking atorvastatin. However, the study did show that participants on atorvastatin showed improvements in levels of inflammation and lipids in the blood (e.g., lower levels of high-sensitivity C-reactive protein, total cholesterol, and low-density lipoprotein [a combination of protein and fat]). There were no differences in overall lupus disease activity.
“This study shows that while statins decrease CRP and lipid levels in young people with SLE as they do in other populations, statins do not have enough of a positive effect to routinely prescribe them for children with lupus,” says Laura E. Schanberg, MD; principal investigator and professor of pediatrics at Duke University Medical Center. “There are risks with all medications, and this data doesn’t convince us that the risks are worth it for all children with lupus.”
One thing the study did convince researchers of is the safety of statins in people with lupus. In this study, atorvastatin was shown to be safe and well-tolerated among participants with no increase in the number of serious side effects in the atorvastatin group compared to the placebo group. “This shows that statins are safe for most people with lupus,” explains Christy Sandborg, MD; co-principal investigator and professor at Stanford University.
This is the first trial studying the use of statins in children with lupus and the longest trial of statins among children, but there is still more work to be done. In particular, there are likely subsets of young people with lupus who will benefit from early statin therapy, and the researchers believe this deserves future investigation. “We think the take home message for pediatric rheumatologists is that they shouldn’t plan on routinely prescribing statins to their patients just yet,” agree Drs. Sandborg and Schanberg.
Editor’s Notes: Laura E. Schanberg, MD will present this research during the ACR Annual Scientific Meeting at the Georgia World Congress Center at 3:00 PM on Wednesday, November 10 in the Thomas J. Murphy Ballroom. Dr. Schanberg and Dr. Sandborg will be available for media questions and briefing at 8:30 AM on Tuesday, November 9 in the on-site press conference room, B 212.
Learn more about living well with rheumatic disease as well as rheumatologists and the role they play in health care.
Presentation Number: L10
Does Atorvastatin Reduce Carotid Atherosclerosis in Pediatric SLE? Results from the Atherosclerosis Prevention in Pediatric Lupus Trial: The Largest Multicenter, Randomized, Double-Blind, Placebo-Controlled Study in Pediatric SLE.
Laura E Schanberg, MD (Department of Pediatrics, Duke University Medical Center, Durham, NC)
Christy I Sandborg, MD 2Pediatric Rheumatology PTD, Stanford Medical Center, Stanford, CA)
Huiman X Barnhart (Duke University Medical Center)
Stacy P. Ardoin (Childhood Arthritis and Rheumatology Research Alliance)
Eric Yow (University Medical Center)
Greg W Evans (Wake Forest University)
Kelly L Mieszkalski (Duke University Medical Center)
Norm T Ilowite (Childhood Arthritis and Rheumatology Research Alliance)
Anne Eberhard (Childhood Arthritis and Rheumatology Research Alliance)
Lisa F Imundo (Childhood Arthritis and Rheumatology Research Alliance)
Yukiko Kimura (Childhood Arthritis and Rheumatology Research Alliance)
Emily von Scheven (Childhood Arthritis and Rheumatology Research Alliance)
Earl Silverman (Childhood Arthritis and Rheumatology Research Alliance)
Suzanne L Bowyer (Childhood Arthritis and Rheumatology Research Alliance)
Lynn Punaro(Childhood Arthritis and Rheumatology Research Alliance)
Nora G Singer (Childhood Arthritis and Rheumatology Research Alliance)
David D Sherry (Childhood Arthritis and Rheumatology Research Alliance)
Deborah McCurdy (Childhood Arthritis and Rheumatology Research Alliance)
Marisa Klein-Gitelman (Childhood Arthritis and Rheumatology Research Alliance)
Carol Wallace (Childhood Arthritis and Rheumatology Research Alliance)
Richard Silver (Childhood Arthritis and Rheumatology Research Alliance)
Linda Wagner-Weiner (Childhood Arthritis and Rheumatology Research Alliance)
Gloria C Higgins (Childhood Arthritis and Rheumatology Research Alliance)
Hermine I Brunner (Childhood Arthritis and Rheumatology Research Alliance)
Lawrence Jung (Childhood Arthritis and Rheumatology Research Alliance)
Jennifer B Soep (Childhood Arthritis and Rheumatology Research Alliance)
Ann M Reed (Childhood Arthritis and Rheumatology Research Alliance)
Purpose: Systemic lupus erythematosus (SLE) is an independent risk factor for premature myocardial infarction and stroke. Given their lifelong exposure to increased atherogenic potential, children and adolescents with SLE are at particularly high risk for developing premature atherosclerosis. Statins reduce cardiovascular morbidity and mortality in the general adult population but statin efficacy in preventing atherosclerosis progression in SLE is not known. The Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial was designed to assess the efficacy and safety of statins in preventing progression of carotid intima medial thickening (CIMT).
Methods: 221 children and adolescents (10-21 yrs) with SLE from 21 Childhood Arthritis and Rheumatology Research Alliance (CARRA) sites were randomized to receive atorvastatin or placebo in addition to hydroxychloroquine and standard care for 36 months. The primary endpoint was progression of mean-mean common CIMT measured by ultrasound. The study was powered to detect a 0.0045 mm/yr difference in CIMT progression between the treatment groups. Secondary endpoints included progression of mean maximal CIMT, other segment or wall specific CIMT endpoints, SLE disease activity and damage outcome measures and health-related quality of life (HR-QOL).
Results: There was no statistically significant difference in the progression of mean-mean common CIMT between the treatment groups (0.0010 mm/yr [placebo] vs. 0.0024 mm/yr [atorvastatin], p = 0.24). Although not reaching statistical significance, the progression of mean maximal CIMT was slower in the atorvastatin group than the placebo group (0.0037 mm/yr vs. 0.0064 mm/yr, p = 0.08). In models adjusting for baseline covariates imbalanced in the two groups or known to impact CIMT, the adjusted difference in mean-mean common CIMT progression rate remained non-significant while the adjusted difference in mean maximal CIMT progression was 0.0042 mm/yr (p = 0.006). The atorvastatin group achieved lower levels of high sensitivity c-reactive protein (p = 0.04), total cholesterol (p = <0.001), and low density lipoprotein (p = <0.001). Changes in measures of HR-QOL, SLE disease activity and damage were similar in both groups as was the frequency of serious adverse events and pre-defined critical safety measures (muscle, liver and neurotoxicity).
Conclusion: APPLE is the largest randomized, placebo-controlled trial ever performed in pediatric SLE, is the first trial completed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA), and is the longest prospective trial assessing statin safety and efficacy in any pediatric population. Atorvastatin treatment did not significantly reduce mean-mean CIMT progression in this population of children and adolescents with SLE. However, the observed trend toward reduced CIMT progression in the atorvastatin group as measured by mean-max CIMT deserves further investigation, including subgroup analyses. Importantly, long-term atorvastatin treatment was well tolerated and safe. In addition, it is possible to successfully enroll and complete a randomized controlled prevention trial in a young SLE cohort.
Disclosure: Laura Schanberg, Bristol-Myers Squibb: advisory board, Pfizer Inc: provided study drug, Research grants; Christy Sandborg, nothing to disclose; Huiman Barnhart, nothing to disclose; Stacy Ardoin, nothing to disclose; Eric Yow, nothing to disclose; Greg Evans, AstraZeneca: Consulting fees, Image Place: Consulting fees; Kelly Mieszkalski,
nothing to disclose; Norm Ilowite, nothing to disclose; Anne Eberhard, nothing to disclose; Lisa Imundo, nothing to disclose; Yukiko Kimura, nothing to disclose; Emily von Scheven, nothing to disclose; Earl Silverman, nothing to disclose; Suzanne Bowyer, nothing to disclose; Lynn Punaro, nothing to disclose; Nora Singer, Pfizer Inc: DSMB, travel monies, part of Pfizer clinical trial; David Sherry, nothing to disclose; Deborah McCurdy, Amgen Inc.: Stock, stock options or bond holdings; Marisa Klein-Gitelman, Abbott Immunology Pharmaceuticals: Research grants, Pfizer Inc: Research grants, UCB, Inc.: Consulting fees; Carol Wallace, Pfizer Inc: Research grants, Richard Silver, nothing to disclose; Linda Wagner-Weiner, nothing to disclose; Gloria Higgins: Abbott Immunology Pharmaceuticals: money to institution via multicenter trial, Immunex: money to institution via multicenter trial, Novartis Pharmaceuticals Corporation: money to institution via multicenter trial, Pfizer Inc: Money to institution via multicenter trial; Hermine Brunner, nothing to disclose; Lawrence Jung, nothing to disclose; Jennifer Soep, nothing to disclose; Ann Reed, nothing to disclose.