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J Am Coll Cardiol, 2005; 46:106-112, doi:10.1016/j.jacc.2005.03.054 © 2005 by the American College of Cardiology Foundation |
,1
,*
* Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, New York, New York
Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
Department of Neurology, Mount Sinai School of Medicine, New York, New York
Manuscript received November 1, 2004; revised manuscript received March 18, 2005, accepted March 22, 2005.
* Reprint requests and correspondence: Dr. Juan J. Badimon, Cardiovascular Biology Research Laboratory, Mount Sinai School of Medicine, One Gustave Levy Place, P.O. Box 1030, New York, New York 10029 (Email: juan.badimon{at}mssm.edu).
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Abstract |
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BACKGROUND: Regression of atherosclerotic lesions by lipid-lowering therapy has been reported.
METHODS: Using a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden.
RESULTS: Both statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p < 0.001). Total cholesterol decreased by 26% versus 33% and LDL-C by 36% versus 46% in the conventional (20 mg) versus aggressive (80 mg) simvastatin groups, respectively. Although the simvastatin 80-mg group had significantly higher baseline TC and LDL-C levels, both groups reached similar absolute values after treatment. A significant reduction in VWA was already observed by 12 months. No difference on vascular effects was detected between the randomized doses. Post-hoc analysis showed that patients reaching mean on-treatment LDL-C 
100 mg/dl had larger decreases in plaque size.
CONCLUSIONS: Effective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin.
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Experimental (1) and clinical (2,3) evidence supports the notion that statins stabilize high-risk (vulnerable) lesions by reducing the lipid content and inflammation of atherosclerotic plaque, thereby increasing the fibrous-muscular/lipid tissue ratio. It has been postulated that statins may reduce atherosclerotic burden, and by stabilizing the atherosclerotic plaques reduce the risk of plaque disruption. Plaque disruption is considered the leading mechanism responsible for the thrombotic complications of atherosclerotic disease (4). On the other hand, it also has been postulated that statins may exert their clinical benefits via lipid-lowering independent or pleiotropic mechanisms (5–7).
The availability of high-resolution imaging modalities has significantly facilitated the possibility of performing in vivo regression studies. Cross-sectional magnetic resonance imaging (MRI) has emerged as the most promising noninvasive technique for longitudinal in vivo studies of large atherosclerotic arteries (8). Its usefulness in studying plaque progression, stabilization, and even regression has been shown in several animal models by several groups. Recently, MRI has been used to image human atherosclerotic lesions in several vascular territories and its accuracy and reproducibility in measuring atherosclerotic plaques has been reported (9).
We have previously reported that despite an early hypolipidemic effect, at least 1 year of treatment was needed to detect significant changes in plaque size in clinically asymptomatic patients (10). Our preliminary results were recently confirmed in a case-control study reporting smaller plaque size, a smaller lipid core, and reduced lipid content in patients treated with an aggressive lipid-altering regimen for 10 years (3). More importantly, prospective angiographic studies showed that simvastatin halted the progression of stenotic coronary lesions (11) and the combination of simvastatin and niacin has the potential to reduce the degree of stenosis (12).
The purpose of this single-center, prospective, randomized trial was to investigate the long-term effect of lipid lowering by simvastatin on early atherosclerotic lesions in humans and to compare the effects of aggressive versus conventional therapy by means of two different dosages of the same statin.
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Methods |
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130 mg/dl and triglycerides 445 mg/dl) and clinically asymptomatic patients. Recruitment started in March 1999, and the study was terminated in March 2002.
Inclusion criteria were based on the pre-existence of atherosclerotic plaques (thoracic aortic wall 4.0 mm and/or carotid wall 2.0 mm thick) detected by carotid B-mode ultrasound, echocardiography, or MRI. Serial MRI studies of the thoracic aorta and carotid arteries were performed at baseline and every 6 months after therapy initiation. This study design allowed each patient to serve as his or her own control, hence offering the opportunity to study progression or regression of the same (or individual) atherosclerotic lesions using MRI.
Exclusion criteria were heart failure, renal or hepatic disease, significant carotid disease, or a clinically significant medical or surgical event within 3 months before study entry. Of 110 patients screened, 51 patients fulfilled the inclusion criteria and were enrolled after providing written consent. Patients were randomized in a double-blind fashion to conventional (simvastatin 20 mg) or aggressive (simvastatin 80 mg) lipid-lowering interventions.
The patient characteristics are summarized in Table 1. Clinical follow-up was done at 6, 12, 24, and 48 weeks and blood samples were drawn at baseline, 6, 12, 24, 48, 72, and 96 weeks to determine lipid levels and safety parameters. The local institutional review board approved the protocol.
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Imaging parameters were: repetition time (TR), 2 R-R intervals; echo time (TE), 12/45 ms (proton density-weighted/T2-weighted); field of view, 12 cm; slice thickness, 3 mm; no interslice gap, acquisition matrix, 256 x 256; 512 zero filling; no phase wrap; number of signal averaged 1/2 (proton density-weighted/T2-weighted); echo-train length, 32; receiver bandwidth, ±64 kHz. A chemical shift suppression pulse was used to suppress the signal from perivascular fat. For the aorta, 25 to 30 transverse images from the origin of the left subclavian artery to the level of the diaphragm were obtained. For the aortic arch, 10 to 12 cross-sectional oblique images (perpendicular to the vessel wall) were acquired. The imaging parameters were similar as for carotid imaging, except: 20-cm field of view and 5-mm slice thickness.
The in-plane resolution was 780 x 780 µm for the aorta and 469 x 469 µm for the carotid artery. The total examination lasted 60 to 90 minutes.
Morphometric analysis. The MR images were transferred to a Macintosh computer for further planimetric analysis. Special attention was given to match images of the same patient at different follow-up time points, using several anatomic landmarks (i.e., carotid bifurcation, top of the aortic arch, origin of the coronaries, pulmonary artery bifurcation, and pulmonary veins) as previously described (9,14). To minimize sub-millimeter errors in the matching of the images at different time points, at least five contiguous MR images per plaque were analyzed and their average was considered for statistical analysis. Computer-assisted morphometric analysis of cross-sectional MR images was used to measure vessel wall dimensions by semiautomatic tracing (Image Pro-Plus, Media Cybernetics, Carlsbad, California). The tracing tool works by following an edge (i.e., boundary) of significant contrast. Lumen area (LA); total vascular area (TVA); minimal, maximal, and mean vessel wall thickness (VWT); and vessel wall area (VWA = TVA – LA) were calculated. The measurements were performed blinded to the patient’s identity and image order. The reproducibility of the VWA measurement has been previously reported (9,10,14). We reported an image-specific error (standard deviation between matched images) of 6 mm2 for aortic and 2 mm2 for carotid images. If the average values of five contiguous images were considered, the error was reduced at 4.5 mm2 for aortic and 1.5 mm2 for carotid images. This corresponds to an error of 2.6% for aortic and 3.5% for carotid plaques. Based on our reproducibility data, we calculated that changes in plaque size of more than 5.2% for aortic and more than 7% for carotid lesions are likely to be accurately measured by MRI (10).
The effects of the lipid-lowering intervention on atherosclerotic lesions were assessed as changes in vessel dimensions versus baseline. A direct effect of simvastatin on normal vessel wall (no plaque visually detectable, maximal VWT <3 mm for aortic and <2 mm for carotid segments) has been previously ruled out by analyzing 28 non-atherosclerotic arterial segments (17 aortic and 11 carotid segments) after 12 months of treatment (10). The difference in VWA was 2.4% (p = 0.8) for aortic and 3.9% (p = 0.3) for carotid segments.
Statistical analysis. Data are presented as mean ± SD. Statistical analysis was performed using analysis of variance for repeated measures or Student’s t test (StatView 4.1, 2002, ABACUS Inc., Cary, North Carolina). A value of p < 0.05 was considered significant.
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The mean follow-up was 18.1 ± 6.3 months. An MRI follow-up was performed in 40 patients at 12 months, in 33 patients at 18 months, and in 20 patients at 24 months.
One patient was lost to follow-up during the first 6 months: a 52-year-old man with no previous episode of angina died suddenly during exercise 3 weeks after starting in the conventional treatment group.
Effect on plasma lipid levels. As expected, simvastatin therapy was associated with a significant reduction in both TC and LDL-C (Fig. 1). For the conventional treatment group, receiving simvastatin 20 mg, the reduction was 25% for TC and 36% for LDL-C. The aggressive treatment group, receiving simvastatin 80 mg, showed an additional 7% reduction in TC, corresponding to a total decrease of 32% versus baseline values. For LDL-C the additional reduction was 10%, corresponding to a total reduction of 46% versus baseline. Simvastatin 80 mg induced a significantly higher percent decrease in TC and LDL-C than simvastatin 20 mg (Fig. 1).
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Effect on plaque size. The effects of both lipid-lowering treatments on carotid and aortic atherosclerotic lesions throughout the study are shown in Figure 2. Overall, statin administration was associated with a significant decrease in VWA over time (analysis of variance p < 0.001) for both aortic and carotid atherosclerotic lesions. At least 12 month of treatment was required before any statistically significant change in VWA could be detected. Aortic VWA decreased by 10% at 12 months and by 15% at 24 months. Carotid VWA decreased by 14% and 18% at 12 and 24 months, respectively. Similar trends were seen for change in maximal VWT, confirming that the changes take place in the thickened areas of the vascular wall, because normal wall did not show any change. The decrease in VWT was 9% at 12 months and 15% at 24 months in aortic lesions. In carotid lesions, VWT decreased by 10% at 12 months and by 17% at 24 months. Aortic lumen increased by 5% and 6% at 18 and 24 months, respectively. Carotid artery lumen increased by 4% and 5%, respectively. No change in lumen size was detected at 6 and 12 months. Similar trends in change over time were seen for both statin dosages. In fact, no difference was seen between the two treatments for any of the vascular measurements.
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The post-hoc analysis of the vascular effects according to the median split of the lipid-lowering effect, independently of the treatment group assignment, showed that the group that reached lower LDL-C levels had the faster decrease in VWA (slope r = –0.62 vs. r = –0.53). Accordingly, the group with the larger percent decrease in LDL-C had a larger decrease in VWA (slope r = –0.58 vs. r = –0.57).
More interesting were the observations when the effects of therapy were analyzed based on the efficacy in achieving the National Cholesterol Education Program (NCEP) goals of LDL-C plasma levels of 100 mg/dl independent of the treatment received. Patients that reached an LDL-C 100 mg/dl showed a larger decrease in plaque size compared with those that did not achieve this cholesterol goal. Patients that reached LDL-C 100 mg/dl had a 17% reduction in aortic VWA, versus a 12% in the group with on-treatment levels of >100 mg/dl LDL-C. This difference was statistically significant (p = 0.027). Similar trends were seen for lesions in the carotid arteries (Fig. 4). An average VWA decrease of 16.5% in patients with LDL-C 100 mg/dl versus a 12% decrease in patients with LDL-C >100 mg/dl was seen (p = 0.36).
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Discussion |
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Recently, Jensen et al. (16) reported similar results in the coronary circulation in patients with hemodynamically non-significant coronary stenoses (<50% stenoses) after 15 months of simvastatin treatment. This intravascular ultrasound (IVUS) study showed that statin treatment induces coronary vessel shrinkage without affecting the lumen during the first year of treatment, which confirms our findings that statin treatment may reverse some of the compensatory enlargement seen in early atherosclerotic lesions (13). More recently, Nissen et al. (17) showed that aggressive lipid-lowering therapy by atorvastatin reduces lesion progression in patients with more severe coronary disease and partial statin pretreatment. These findings confirm our hypothesis that atherosclerotic plaque regression is possible by lipid-lowering interventions. These effective interventions, by removing the intravascular lipid deposition, would lead not only to plaque reduction but also to its stabilization. These observations reinforce our hypothesis that early lipid-lowering treatment before the atherosclerotic disease progresses to clinically manifest lesions would render faster and more efficient benefits. Further efforts should be made to provide early detection of atherosclerosis, better patient risk stratification, and clearer definition of the optimal time point at which to intervene with the most adequate treatment. In fact, little is known about the natural history of atherosclerosis and the rate of progression of stable disease, crucial information for better interpretation of the available results of different interventions in atherosclerosis. The availability of the new non-invasive imaging modalities may make a significant impact on these unanswered questions.
Surprisingly, we found similar trends on plaque size effect in patients treated with 20 mg and 80 mg simvastatin, without any substantial difference between the groups. A possible explanation for these unexpected results lies in the difference between the baseline lipid levels for the two groups. In fact, patients assigned to the aggressive intervention had significantly higher LDL-C levels at baseline. Although the 80-mg dose had a higher relative hypolipidemic effect than the 20-mg dose (LDL-C reduction of 46% vs. 36%, p < 0.01, Fig. 1B), both groups reached similar lipid levels after treatment (Fig. 1A).
The results of our study support the hypothesis that the observed clinical benefits of statins seem to be mediated predominantly via their hypolipidemic effect. In fact, the stratification of the results in a post-hoc analysis, according to the LDL-C, showed that patients who reached an LDL-C 100 mg/dl (2.6 mmol/l) had greater regression of atherosclerotic lesions (Fig. 4). These data support the LDL-C goal defined by the NCEP Adult Treatment Panel (ATP)-III guidelines for secondary prophylaxis in CHD and CHD risk equivalents and should further stimulate the medical community to increase the effort toward this goal. Our data support the increasing consensus that "lower is better" and raise the question of whether stricter new guidelines, with lower lipid levels, are required to further reduce the socioeconomic impact of cardiovascular diseases.
Interestingly, despite the early maximal hypolipidemic effect (obtained after 6 weeks of treatment), at least 12 months of treatment is needed before detecting significant changes in lesion characteristics. In the recently published Heart Protection Study, a significant benefit of simvastatin in a dose of 40 mg was shown independently of the baseline lipid levels (18). Similar to previous prevention trials, the clinical benefit of statin treatment became evident only after 12 months of treatment (18). The changes in plaque size shown in our study are potentially expressive of the transformation in plaque composition leading to a stabilization of the lesion. This hypothesis is supported by several experimental and observational studies showing lipid depletion in atherosclerotic lesions after prolonged lipid lowering either by statin or by diet (1,9,12,19). An important question that could not be addressed by this study is whether the observed plaque regression could be achieved at an earlier time in patients with more advanced atherosclerotic lesions.
The degree of LDL-C reduction seems a good predictor for plaque regression. Three recently published studies investigated the effects of aggressive versus conventional lipid-lowering interventions in a population with more advanced atherosclerosis. The IVUS-based Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial (17) established the benefits of a more aggressive hypolipidemic intervention in coronary lesions, whereas the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial (20), an event-based study in patients with acute coronary syndromes, showed a significant reduction in the number of cardiovascular events by an aggressive lipid-lowering strategy compared with a conventional approach. Surprisingly, disappointing results from the Phase Z of the A to Z trial (21) were more recently reported. This large, multicenter, double-blind study in 4,497 acute coronary syndrome patients did not confirm the benefit of an early initiation of an aggressive simvastatin regiment and resulted only in a favorable trend toward reduction of major cardiovascular events.
The hypolipidemic effect of statins and lipid removal from the atherosclerotic lesions are probably the major mechanisms responsible for the clinical benefits observed in these trials. A possible explanation for the different results between our study and the REVERSAL study rests in the different patient characteristics and the fact that we used two dosages of the same statin, whereas the REVERSAL study used two different statins. This observation, added to the contrasting results of the PROVE-IT trial (20) and Phase Z of the A to Z trial (21), also raises concerns regarding whether all of the statins are equal. Our goal was to study early-stage atherosclerotic lesions. Therefore, we selected a cohort of asymptomatic and newly diagnosed hypercholesterolemic, statin-naive patients, who are more likely to have smaller and less fibrotic lesions.
Further studies should be performed to define the ideal "cholesterol level threshold" and the real benefits of aggressive versus conventional lipid-lowering therapy when using the same drug. Several ongoing clinical trials (Incremental Decrease in End Points through Aggressive Lipid Lowering [IDEAL], Treating to New Target [TNT], Study of Effectiveness of Additional Reductions in Cholesterol and Homocysteine [SEARCH]) will probably provide an answer for this dilemma. The potential of other lipid-modifying therapies as well as approaches aimed at modifying plaque composition should be further elucidated. In 1990, Badimon et al. (22) described the anti-atherogenic effects of the administration of homologous high-density lipoprotein (HDL) in an experimental model of atherosclerosis. Spieker et al. (23) recently reported rapid normalization of endothelium-dependent vasodilation by increasing nitric oxide bioavailability after infusion of reconstituted HDL infusion in hyperlipidemic patients. Regression of human atherosclerotic lesions has been shown by IVUS after five weekly infusions of recombinant apolipoprotein A-I Milano (24). These observations raise the question of whether a combination of an LDL-lowering and HDL-raising approach could be the most effective intervention for regressing atherosclerotic lesions. The potential effectiveness of combining two interventions with different mechanisms of action has been recently investigated by our group at the preclinical level by combining a statin with a selective peroxisome proliferator-activated receptor-gamma agonist (25).
In conclusion, effective and protracted lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. Our data strongly support the efficacy and potential clinical benefits of an effective and aggressive lipid-lowering intervention on atherosclerotic disease. Plaque regression was more related to the degree of LDL-C reduction rather than to the dose of statin, because no difference between high- and moderate-dose simvastatin was detected.
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Acknowledgments |
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Footnotes |
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1 Drs. Corti and Muntwyler are currently working in the Department of Cardiology, University Hospital Zurich, Switzerland. 
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