ARBITER Trial
Abstracts & Commentary
Synopsis: Marked LDL reduction (< 100 mg/dL) with a high potency statin provides superior efficacy for atherosclerosis regression at 1 year.
Sources: Taylor A, et al. Circulation. 2002;106:2055-2060; Shah P. Circulation. 2002;106:2039-2040.
This study sought to evaluate whether treatment with 2 statins of differing potency would have differing effects on carotid intima-media thickness (IMT) in a cohort of dyslipidemic individuals. Taylor and colleagues also hoped to identify whether statins are effective through a class effect or through nonlipid actions. Healthy and coronary artery disease (CAD) individuals who met NCEP-ATP II criteria for pharmacologic therapy were randomized to either of 2 statins, pravastatin 40 mg daily (prava) or atorvastatin 80 mg daily (atorva). Approximately 46% of individuals had a history of CAD; these subjects are not discussed further in the paper. Treatment was carried out for 12 months with reasonably good compliance in the 138 patients who completed the study. The primary end point was a change in the mean common carotid IMT at 1 year. Secondary end points included a composite of multiple clinical end points. Standard research quality B-mode ultrasound was used. An experienced observer in the standard fashion read all images blindly. Reproducibility, precision, and reliability of this method were high. Standard lipid determinations as well as C-reactive protein (CRP) and fibrinogen were measured at baseline, 3, and 12 months. The average age cohort was 60 years and 70% were male. Baseline mean total cholesterol was 232 ± 42 mg/dL, and LDL cholesterol was 152 ± 34 mg/dL. Triglycerides were 206 and HDL was 49. Baseline CRP was 0.41 and fibrinogen was approximately 380. Carotid IMT was 0.627 ± 0.189 mm (range, 0.32-1.36 mm). The groups were equally matched at baseline.
Results
Atorvastatin produced greater reductions than prava in total and LDL cholesterol as well as triglyceride. After 12 months on-therapy LDL-C was 76 ± 23 mg/dL on atorva, a 48% decrease from baseline; prava lowered LDL to 110 ± 30 mg/dL, a 27% decrease from baseline. CRP was reduced by atorva and prava, but more so with atorva. Carotid IMT decreased in the atorva group, which was significantly different from prava (P = 0.03). There was overall regression with atorva during the 12-month period, whereas carotid IMT in the prava group was essentially unchanged; P = 0.03. Maximum IMT also decreased more with atorva; the differences did not reach significance. By the end of the study, mean prava IMT actually had risen above baseline, whereas the atorva IMT measurements continued to fall at 6 and 12 months. Prava-induced regression was seen in 27/70 prava patients (39%) vs 37/68 of atorva patients (54%). There were no significant side effects in the patients in either group, and no difference in cardiovascular events. Fibrinogen did not change but CRP decreased at 12 months in all patients, dropping by 50% in the atorva cohort.
Taylor et al concluded that atorva was quite effective, with marked lowering of LDL cholesterol and an associated reduction in Carotid IMT. They stated that the data "supports, but does not prove, the potential of high potency, synthetic statins . . . to prevent adverse cardiovascular events." They point out that there are no major published outcome trials with atorva, and emphasize that the BELLES, REVERSAL, and PROVE IT trials are underway, which will provide clinical end points using the same 2 drugs at the same dosage levels. They further concluded that the reduction in both CRP and carotid IMT indicate that statin action on CRP levels is not independent from LDL lowering. They believe that the effects on carotid IMT with high-dose atorva indicate support the belief that "marked LDL reduction with synthetic statins may provide enhanced reduction in clinical coronary event rates."
Comment by Jonathan Abrams, MD
These data are of interest but certainly not surprising. A large number of regression trials have previously been reported demonstrating a decrease in carotid as well coronary atherosclerosis when measured by highly sensitive methodology. In many earlier trials, event rates were surprisingly reduced in the active treatment group, perhaps the first suggestion that the results of the then ongoing randomized statin trials would be positive with respect to clinical end point reduction. These assumptions were proven to be absolutely correct with release of the 4S trial, and subsequently the LIPID and CARE studies. A later regression study (ASAP) in familial hypercholesterolemia showed a greater regression in coronary atherosclerosis with atorva 80 mg compared to 40 mg of simvastatin (Lancet. 2001;357:577). The degree of regression of atherosclerosis in the coronary and carotid circulations in all these reports is quite small, yet regression is generally considered to be a surrogate for significant stabilization of vascular disease in dyslipidemic individuals. Whether the event reductions seen in the RCT mentioned above are due solely to lipid lowering is unclear; Taylor et al suggest that there may be pleiotropic effects with atorvastatin. It is impossible to separate out the effects of LDL cholesterol lowering from putative pleiotropic actions. Important issues that remain unresolved include how low should LDL cholesterol be reduced with lipid therapy and do subjects at risk but with low LDL cholesterol need therapy. The recently published Heart Protection Study confirms that all cohorts at increased vascular risk benefited, including the larger cohort with a high baseline LDL cholesterol as well as the smaller number of individuals who had low initial lipid levels, in particular, from a baseline LDL cholesterol < 100 (Clinical Cardiology Alert. 2002;21[8]:57-59). In the current study, the LDL level was reduced by high-dose atorva to a mean of 76 mg/dL, which is about as low as seen in any trial to date. This issue is becoming increasingly important, and hopefully some light will be shed on the value of reaching various target LDL levels with the completion of the several randomized trials mentioned above that compare prava with atorva. In an accompanying editorial, Dr. Shah emphasizes that both groups demonstrated regression, raising "the possibility that regression could occur without marked LDL lowering." Shah is not convinced that the ARBITER data are strong enough to determine how far LDL cholesterol should be reduced. He, like many experts, believes that lower is better. He suggests that other lipid modification approaches, such as increasing HDL cholesterol, are also anti-atherogenic.
In conclusion, this study, while with predictable results, is another nail in the hypercholesterolemia coffin. A robust reduction in total LDL cholesterol (as well as triglycerides) appears to stop carotid atherosclerosis in its tracks in many but not all subjects. These favorable results were directionally similar with pravastatin, but significantly more potent with substantially more lipid modification with atorva. The era of treating everyone with vascular disease with lipid modifying agents appears to be close at hand!
Dr. Abrams is Professor of Medicine Division of Cardiology University of New Mexico, Albuquerque, NM.
This study sought to evaluate whether treatment with 2 statins of differing potency would have differing effects on carotid intima-media thickness (IMT) in a cohort of dyslipidemic individuals.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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