Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM
JAMA. 2006;295(13):1556-1565.
Background:
The optimal target levels for low-density lipoprotein cholesterol for secondary prevention remain controversial. Several recent clinical trials have reported that more intensive statin therapy results in a greater reduction in adverse cardiovascular outcomes compared with more moderate treatment goals. In parallel, imaging studies have examined the effects of anti-atherosclerosis therapies on the progression of atherosclerosis. Previous intravascular ultrasound (IVUS) trials have demonstrated slowing or halting of atherosclerosis progression with statin therapy; however, none of the major trials have provided convincing evidence of the regression of atherosclerosis.
Objective:
To assess whether very intensive statin therapy could result in the regression of coronary atherosclerosis as determined by IVUS imaging.
Methods:
Patients who required coronary angiography for a clinical indication and were statin-naive were recruited for the study. Inclusion required a demonstration of at least 1 coronary vessel with >20% to <=50% luminal narrowing. Patients underwent baseline coronary IVUS examination. All patients received intensive statin therapy with rosuvastatin 40 mg/d for 24 months, after which IVUS examination of the target vessel was repeated. IVUS image analyses were performed as a pair using a blinded randomized sequence technique. Two primary efficacy parameters were prespecified: the change in percent atheroma volume and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also evaluated.
Results:
Five hundred seven subjects were enrolled in the study, with 349 having evaluable IVUS examinations both at baseline and follow-up. The mean baseline low-density lipoprotein cholesterol level was 130.4 +/- 34.3 mg/dL; this dropped to 60.8 +/- 20.0 mg/dL at follow-up, which equals to a mean reduction of 53.2% (P < .001).Approximately 75% of patients achieved a mean low-density lipoprotein cholesterol level of <70 mg/dL during treatment. Mean high-density lipoprotein cholesterol level at baseline was 43.1 +/- 11.1 mg/dL; this increased to 49.0 +/- 12.6 mg/dL during follow-up, which represents a mean increase of 14.7% (P < .001). The mean change in atheroma volume for the entire vessel was -0.98% (confidence interval -1.21% to -0.53%, P < .001 vs baseline). The mean change in atheroma volume in the most diseased 10-mm subsegment was -6.1 +/- 10.1 [mu]L (confidence interval -6.8 to -4.0 [mu]L, P < .001 vs baseline). There was a -6.8% median change in total atheroma volume (P < .001). The treatment regimen was well tolerated, and adverse events were infrequent and similar to those seen in other statin trials.
Discussion:
Very high-intensity statin therapy resulted in significant regression of atherosclerosis for all 3 prespecified IVUS measures of coronary disease burden. Atherosclerosis is currently viewed as a progressive disease for which even the most active therapies merely slow the progression of the disease. This study suggests amore optimistic strategy, in which very aggressive lipid-lowering therapies can potentially reverse the atherosclerotic disease process. Further studies are needed to determine whether these observed changes as described by IVUS will translate into a reduction in coronary morbidity and mortality.
Comment:
This article received significant attention in the lay press when it was published. Although this work is exciting, as clinicians, we should temper enthusiasm for very aggressive lipid-lowering strategies by understanding that the changes reported in this trial represented only a modest decrease in mean atheroma volume (from 39.6% to 38.6%) and in mean atheroma volume in the most diseased 10-mm subsegment (from 65 to 59 [mu]L). Whether these modest changes translate to clinical outcomes remain to be determined. We are still a long way away from offering our patients true "treatment" of atherosclerosis as suggested in this article, and the predominant effect of lipid modulation as it relates to plaque stabilization needs to be conveyed to our patients.
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