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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

J Clin Hypertens (Greenwich). 2011;13:492–496.©2011 Wiley Periodicals, Inc.

Intravascular ultrasound (IVUS) is a novel technique that provides an accurate and reproducible method to measure atheroma burden. Statin drugs reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality. Studies assessing the effect of statin treatment on atheroma burden have shown conflicting results. Hence, this meta-analysis was conducted to evaluate the impact of statin therapy on coronary atherosclerosis progression. A systematic search using PubMed, EMBASE, and Cochrane Library databases was performed. Heterogeneity of the studies was analyzed by Cochran’s Q statistics. The significance of common treatment effect was assessed by computing common mean difference between the control and treatment groups. A two-sided α error of <0.05 was considered statistically significant (P<.05). Eight trials composed of 919 patients including a placebo group with 458 patients and a treatment group with 461 patients were used. Characteristics of both groups at baseline were similar without any significant difference between them. In the pooled analysis, the common mean difference of coronary atheroma volume between statin therapy and the placebo arm was −3.573 (confidence interval, −4.46 to −2.68; P<.01). This meta-analysis demonstrates that treatment with statins not only slows atherosclerotic plaque progression but may also lead to plaque regression.

Therapy with high doses of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG CoA) inhibitors (statins) reduces both atherogenic lipoproteins and cardiovascular morbidity and mortality.1,2 Studies have shown that intensive statin therapy is more effective than moderate therapy in reducing the progression of atherosclerosis as determined by measuring carotid intimal medial thickness or assessing atheroma burden using intravascular ultrasound (IVUS).3–5

Angiography plays a pivotal role in the selection of patients for revascularization and has been widely used to measure the efficacy of anti-atherosclerotic drug therapies.6–8 However, angiography depicts a silhouette of the coronary lumen and does not directly image the atheroma within the vessel wall, where anti-atherosclerotic therapies show their effects. The recent application of IVUS in progression-regression trials enabled systematic assessment of the effects of such therapies on various components of the vessel, including the atheroma itself.4,9–11 IVUS provides an accurate and reproducible method to measure atheroma burden and can be used to evaluate progression of coronary atherosclerosis. IVUS is a particularly good method for assessing atherosclerosis because it allows measurement of atheroma burden, not just luminal narrowing.12 IVUS allows the earlier stage of eccentric growth and intramural atheroma formation to be quantified and followed.13 Therefore, many recent studies have used this tool to measure the effects of various anti-atherosclerotic therapies on coronary atheroma burden.

However, studies assessing the effect of statin treatment on atheroma burden have shown conflicting results. Hence, this meta-analysis was conducted to evaluate the impact of statin therapy on coronary atherosclerosis progression.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Literature Search

We performed this review in accordance with the Quality of Reporting of Meta-Analysis (QUOROM) statement and the Consolidated Standards of Reporting Trials (CONSORT) Group recommendations.14 A computerized search was performed to identify all relevant studies published in the English language through January 2009 in EMBASE, CINAHL, PubMed, and Cochrane databases. We also searched for relevant review articles and their bibliographies for articles. The following search terms were used: intravascular coronary ultrasound, simvastatin, atorvastatin, rosuvastatin, pravastatin, HMG CoA reductase inhibitors, and coronary atherosclerosis.

Study Selection

There was a written protocol with explicit inclusion and exclusion criteria that was followed for all articles screened. All titles and abstracts from the results of our computerized search were reviewed by the authors for potential inclusion in our study. We also went into the related links of all relevant articles. In addition to our computerized search, we manually reviewed the reference list of all retrieved articles to complete our search. The study selection process is explained in the Results section. Studies that were not performed in human participants, were not randomized, were published in non–peer-reviewed journals, or that had inadequate follow-up were excluded from our analysis.

Data Abstraction

After identifying all relevant articles, we extracted characteristics of the study (author, year, design, duration, sample size, statin use, and follow-up percentage) and participants (age, sex). Two reviewers independently extracted data and assessed outcomes. The inter-rater agreement was 90%, and disagreements were resolved by consensus. Our primary end point of interest was progression/regression of coronary atherosclerotic burden evaluated by IVUS volumetric analysis.

Statistical Analysis

A systematic review of the literature revealed 8 eligible studies. For the purpose of meta-analysis, heterogeneity of the studies was analyzed by the Cochran’s Q statistics, and I2 was computed to quantify heterogeneity. After running the chi square test, if the P value indicated statistical heterogeneity, the analysis was performed using the random effects model, otherwise, the fixed effects model was used. The significance of common treatment effect was assessed by computing common mean difference between the control and treatment groups. A two-sided α error of <.05 was considered statistically significant (P<.05).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Literature Search

A total of 74 potentially relevant studies were identified and screened for retrieval. After title and abstract screening, 49 studies were excluded and the remaining 25 studies were retrieved for a more detailed evaluation. Finally, a detailed review of 19 clinical studies was performed. Of these 19 clinical studies, 8 were excluded as they did not meet inclusion criteria (because the data were repeated from previously published studies or no data on the outcome was available). Three studies15–17 used cross-sectional area and not plaque volume to assess the atheroma burden and were therefore excluded. Thus, 8 studies were included in our meta-analysis.4,10,18–22

Overview of Studies and Patient Characteristics

We performed a meta-analysis on 8 recent clinical trials. All included trials used plaque volume as the measure of atheroma burden before and after statin therapy. The total number of cases in all 8 studies was 919, with 458 controls and 461 cases. Statins used were atorvastatin in 5 trials,4,10,19–21 simvastatin in 1 trial,18 and pravastatin in 2 trials.21,22 The characteristics of the studies included in the meta-analysis are listed in Table I.

Table I.   Study Characteristics
Study, yearDesignSample SizeStatin RegimenFollow-Up, moMean Age, yMen, %
PlaceboTreatmentPlaceboTreatmentPlaceboTreatment
  1. Abbreviations: GAIN, German Atorvastatin Intravascular Ultrasound study; NA, not available; RCT, randomized controlled trial; REVERSAL, Reversal of Atherosclerosis With Aggressive Lipid Lowering study.

REVERSAL, 2006RCT249253Atorvastatin1855.8±9.155.3±10.669.272.6
ESTABLISH, 2004RCT3535Atorvastatin662.5±11.261.3±10.185.785.7
Yokoyama et al, 2005RCT2220Atorvastatin664.4±8.762.1±10.290.990
Kawasaki et al, 2005RCT1718Pravastatin666±6.467±7.882.372.2
Kawasaki et al, 2005RCT1717Atorvastatin666±6.466±8.782.370.6
Takagi et al, 1997RCT1213Pravastatin3656±1156±10NANA
GAIN, 2001RCT6665Atorvastatin1259.8±7.260.7±8.98585
Jensen et al, 2004Open non–placebo-controlled studyNA40Simvastatin12NA57.7±8.8NA100

Ultrasound Examination

A baseline IVUS was followed by a repeat IVUS after 6 months in the ESTABLISH trial,10 12 months in the GAIN19 and Jensen and colleagues18 trials, and 18 months in the Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) trial.4 Every study used the same IVUS imaging catheter at baseline and follow-up. All IVUS investigations were performed after intracoronary administration of nitrates in all studies. Cine runs, before and during contrast injection, were performed to define the position of the catheter distal to an identifiable side branch.

LDL Lowering

After treatment with statins (mean treatment duration of 12.5 months) there was a significant reduction in the mean low-density lipoprotein (LDL) (before treatment 151.9±15.8 mg/dL vs after treatment 91.9±18.7 mg/dL; P<.001; N=461), and total cholesterol levels (before treatment 227±21.3 mg/dL vs after treatment 167±21.67 mg/dL; P<.001; N=461) (Figure 1 and Table II).

image

Figure 1.  Lipid lowering in the placebo and treatment groups. LDL indicates low-density lipoprotein.

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Table II.   Baseline and Change in Total and LDL Cholesterol Values
Study, yearBaseline Total Cholesterol, mg/dLFollow-Up Total Cholesterol, mg/dLBaseline LDL Cholesterol, mg/dLFollow-Up LDL Cholesterol, mg/dL
PlaceboTreatmentPlaceboTreatmentPlaceboTreatmentPlaceboTreatment
  1. Abbreviations: GAIN, German Atorvastatin Intravascular Ultrasound study; LDL, low-density lipoprotein; REVERSAL, Reversal of Atherosclerosis With Aggressive Lipid Lowering study.

REVERSAL, 2006232.6±34.1231.8±34.2187.5±32.2151.3±38.9150.2±25.9150.2±27.9110.4±25.878.9±30.2
ESTABLISH, 2004190.7±42.8191.8±35.7190.9±29.7141.1±29.1123.9±35.3124.6±34.5119.4±24.670±25
Yokoyama et al, 2005241198±17240156±26152133±1314987±29
Kawasaki et al (pravastatin), 2005241±27250±22240±46196±23152±20149±19149±24102±13
Kawasaki et al (atorvastatin), 2005241±27244±21240±46174±22152±20155±22149±2495±15
Takagi et al, 1997230.1±11.6237.1±15.4220.8±19.3199.6±25.9163.7±18.5176.4±19.6148.6±22.4131.7±26.6
GAIN, 2001242±48228±39215±54156±35166±47155±34140±4886±30
Jensen et al, 2004239.3±33.9239.3±33.9239.3±33.2162.1±29.3158.3±30.5158.3±30.5154.4±26.284.9±22

Effect of Statin Therapy on Coronary Plaque Volume

In the pooled analysis, the common mean difference of coronary atheroma volume between statin therapy and placebo was −3.573 (confidence interval [CI], −4.46 to −2.68; P<.01) (Figure 2). This indicates that statin therapy has a negative impact on plaque volume that was statistically significant. In the trials showing plaque regression (ESTABLISH and Jensen and colleagues; N=150) there was an average 8.7% reduction in plaque volume after treatment with statins (mean treatment duration of 14 months). Two trials (REVERSAL and GAIN; N=301) showed slower plaque progression in the aggressively treated vs moderately or mildly treated groups (percent increase in plaque volume in the treatment group was 3.3% vs 8.6% in the placebo group).

image

Figure 2.  Change in plaque volume with statin therapy: mean difference between treatment and control. CI indicates confidence interval; REVERSAL, Reversal of Atherosclerosis With Aggressive Lipid Lowering study; GAIN, German Atorvastatin Intravascular Ultrasound study.

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

We found in our meta-analysis that treatment with statins in high-risk patients with diabetes mellitus or coronary heart disease, irrespective of their background treatment, not only slows the progression, but also leads to regression of carotid atherosclerosis as measured by IVUS. In the trials10,18 showing plaque regression (ESTABLISH and Jensen and colleagues; N=150), there was an average 8.7% reduction in plaque volume after treatment with statins (mean treatment duration of 14 months). The REVERSAL and GAIN (N=301) trials4,19 showed a slower rate of plaque progression in the aggressively treated vs placebo groups (percent increase in plaque volume in the aggressive treatment group was 3.3% vs 8.6% in the placebo group).

Epidemiologic evidence has established a strong relationship between elevated levels of atherogenic lipoproteins, particularly LDL cholesterol, and the risk of death and complications from cardiovascular causes. Lipid-lowering therapy with statins is one of the first-line management strategies in the management of any patient with atherosclerotic disease. All forms of cholesterol reduction, including physical removal by apheresis, surgery to prevent cholesterol uptake (program on surgical correction of hyperlipidemia),23 and dietary restriction,24 reduce rates of atheroma progression as measured by the coronary mean lumen diameter on quantitative coronary angiography. Statins have shown consistent effects in reducing the progression of coronary atheroma as measured on QCA and similar results on carotid atheroma as measured by intima media thickness in trials such as the Pravastatin Lipids and Carotid Arteries–II (PLAC-II) study25 and the Kuopio Atherosclerosis Prevention Study (KAPS).26

There was a significant reduction in both total cholesterol and LDL cholesterol from baseline after statin therapy, and this correlated with the reduction in atheroma burden. This finding emphasizes the importance of aggressive lipid lowering. Moreover, these trials included both symptomatic and asymptomatic patients, implying that there are not only early beneficial effects of aggressive lipid lowering but that being late is never too late. However, the majority of patients included in these trials were men and this indicates that care should be taken while dealing with women, as the results of our meta-analysis may not be applicable to the female population.

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

As with any meta-analysis, our study has some limitations. First, we included only published data and therefore there is a potential of publication bias. Second, both symptomatic and asymptomatic patients were included in these trials. Third, the methodology used for measurement of coronary atheroma was different in the studies, which may lead to detection bias. However, because serial measurements of coronary atheroma were done and the mean difference was taken for analyzing the effect of statin therapy in individual studies, the effect of this bias seems to be small. Lastly, some of the trials included were small and so were not powered enough to detect significant benefit from intervention studied.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

This meta-analysis demonstrates that treatment with statins not only slows atherosclerotic plaque progression but may also lead to plaque regression.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Funding:  No funding was received in support of our study.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References
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