Systemic Lupus Erythematosus
Abstract 1025: Lupus Atherosclerosis Prevention Study (LAPS): A Randomized Double Blind Placebo Controlled Trial of Atorvastatin Versus Placebo
Authors: Michelle Petri1, Adnan N. Kiani2, Wendy Post2, Laurence Magder3. 1Johns Hopkins University, School of Medicine, Baltimore, MD; 2Johns Hopkins University, Baltimore, MD; 3University of Maryland, Baltimore, MD
Background: Much as we need new FDA-Approved treatments for active lupus, we also need treatments to prevent the major long-term morbidity of lupus, accelerated atherosclerosis. In women with SLE between the ages of 35 and 44 the risk of myocardial infarction is increased 50-fold. Not all of the increased risk can be explained from traditional risk factors. Among traditional risk factors, however, hypertension and obesity are important. Over half of SLE patients with cardiovascular risk factors, though, have normal lipid profiles.
Trying to determine the “lupus factor” that drives atherosclerosis has been difficult. The usual factors that tell us who will have a severe lupus course, such as anti-dsDNA or low complement, do not predict later atherosclerosis. In addition, although antiphospholipid antibodies do predict myocardial infarction (a thrombotic event), they do not predict subclinical atherosclerosis.
Subclinical atherosclerosis can be measured in several ways, including carotid intima media thickness, carotid plaque, or coronary calcium. Past studies have confirmed that SLE patients have higher levels of subclinical atherosclerosis than the general population. Subclinical measures need to be used in intervention trials in SLE, because the number of patients length of observation time necessary to observe actual cardiovascular events would be prohibitive.
Statins seem a natural choice for an intervention trial in SLE. In the general population we know that they reduce myocardial infarction, even in those with normal lipid levels. They have an anti-inflammatory effect, in that they reduce high sensitivity CRP and other measures of inflammation. This anti-inflammatory effect is thought to be important both in the prevention of atherosclerotic progression and in stabilizing the plaque, thereby preventing plaque rupture. Finally, in several autoimmune diseases, namely rheumatoid arthritis and multiple sclerosis, statins may have a beneficial effect on disease activity.
Purpose: This randomized clinical trial assessed whether atorvastatin could prevent worsening in surrogate measures of atherosclerosis in SLE.
Methods: 200 SLE patients were randomized to atorvastatin 40 mg or to placebo. Patients who needed statins for clinical reasons were excluded. Patients with baseline elevations of liver function tests or muscle enzymes were also excluded. Patients at risk for pregnancy or planning to become pregnant were excluded, as well. At baseline, patients had a helical CT for measurement of coronary calcium, the primary outcome. Carotid duplex was performed for carotid intima media thickness and carotid plaque (secondary outcome measures). These tests were repeated at 2 years. Disease activity was followed by the SELENA SLEDAI every 3 months.
Results: The measures of subclinical atherosclerosis did increase during the two years of follow-up. However, there was no difference in the mean coronary calcium (the primary outcome). Carotid IMT or carotid plaque (the secondary outcomes) or in disease activity. A post-hoc categorical analysis of carotid IMT was in favor of atorvastatin. Total cholesterol was reduced significantly in the atorvastatin group. High sensitivity CRP was actually higher in the atorvastatin group. Abnormalities of liver function tests occurred more often in the atorvastatin group.
Conclusion: Atorvastatin does not reduce progression of subclinical atherosclerosis as defined a priori in this clinical trial. The post-hoc analysis of categories of carotid IMT (same, worse, improved) showed less worsening in the atorvastatin group, but would need to be confirmed prospectively in another trial. There was no benefit in disease activity.
Editorial Comment: In the general population, inflammation is as important as hyperlipidemia in the prediction of atherosclerotic cardiovascular disease. Statins reduce hsCRP, the accepted marker for the inflammatory risk of atherosclerosis. High sensitivity CRP is increased in SLE. Thus, one would have expected statins to be a “slam dunk” in their benefit for atherosclerosis in lupus.
What went wrong? SLE patients who needed statins for hyperlipidemia were excluded; this study does not negate the benefit of statins in this group. This study used a moderate dose of a potent statin; given the issue of elevated liver function tests, a higher dose would not have been practical. Basically, the immunomodulatory effects of the statin used had no benefit on atherosclerosis or disease activity. Lupus experts will have to go back to the drawing board, because no other obvious drug candidate for intervention exists.