Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia qmRSYqFXNBDYHWFCdNgZWZh S0066-782X2015002000011 S0066-782X2015005050050 10.5935/abc.20150050 Original Articles Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression Masson Walter 1 2 Siniawski Daniel 1 2 Lobo Martín 1 Molinero Graciela 1 Giorgi Mariano 1 Huerín Melina 1 Sociedad Argentina de Cardiología Consejo de Epidemiología y Prevención Cardiovascular Buenos Aires Argentina Consejo de Epidemiología y Prevención Cardiovascular de la Sociedad Argentina de Cardiología, Buenos Aires - Argentina Hospital Italiano de Buenos Aires Buenos Aires Argentina Hospital Italiano de Buenos Aires, Buenos Aires - Argentina Universidad de Buenos Aires Mailing Address: Walter Masson, Hospita Italiano de Buenos Aires. Gascon 450, Ciudad Autónoma de Buenos Aires. Postal Code 1416, Buenos Aires – Argentina. E-mail: walter.masson@hospitalitaliano.org.ar

Conception and design of the research: Masson W, Siniawski D, Huerín M. Acquisition of data: Masson W, Lobo M, Molinero G, Huerín M. Analysis and interpretation of the data: Masson W, Siniawski D, Lobo M, Giorgi M, Huerín M. Statistical analysis: Masson W, Lobo M. Writing of the manuscript: Masson W, Siniawski D, Molinero G, Huerín M. Critical revision of the manuscript for intellectual content: Masson W, Siniawski D, Lobo M, Molinero G, Giorgi M, Huerín M. Supervision / as the major investigador: Masson W.

Dr. Giorgi reported receiving an educational grant from Pfizer and BMS.

 07 2015 19 05 2015 105 1 11 19 29 10 2014 09 03 2015 18 03 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License which permits unrestricted noncommercial use, distribution, and reproduction in any medium provided the original work is properly cited. Background:

Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers.

 Objective:

To assess the association between changes in lipid markers and regression of CPV using published data.

 Methods:

We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV.

 Results:

Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume.

 Conclusion:

A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.

 Cardiovascular Diseases Atherosclerosis / physiopathology Cholesterol, LDL Apolipoprotein B/ therapeutic use Lipoproteins, LDL Introduction

In the last twenty years, strong evidence from clinical studies demonstrated that the reduction of low-density lipoprotein cholesterol (LDL-C) with different lipid-lowering drugs, mainly HMG-CoA reductase inhibitors (statins), is critical in decreasing the incidence of coronary events 1 , 2. Similarly, different studies showed an association between LDL-C reduction and regression of coronary plaque measured by intravascular ultrasound (IVUS)3 , 4. A recent meta-regression study has shown that pharmacologically induced regression of atherosclerotic plaque burden is associated with clinically significant reduction of myocardial infarction and revascularization5.

Previous reports inferred a linear association between LDL-C and changes in coronary plaque volume (CPV) assessed by IVUS6 , 7. However, these publications included a small number of studies and did not explore the relationship with other lipid markers like non–high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (ApoB), which in several reports were related more closely to the risk of vascular disease than LDL-C itself8 , 9.

In this context, the aim of our study was to assess the association between changes in plasma levels of lipid markers (LDL-C, non-HDL-C, and ApoB) and the regression of coronary atherosclerotic plaque measured by IVUS using published data.

 Methods

Two reviewers independently searched the electronic databases PubMed/Medline, EMBASE and Cochrane Clinical Trials using the following terms: "intravascular ultrasound", "IVUS", "regression of atherosclerosis", and "statins". Studies were selected according to the following criteria: a) trials that explored the effect of one or more different lipid-lowering drugs (or different dosages) on the variation in CPV evaluated by IVUS (total atheroma volume), b) at least three months of follow-up, and c) availability of plaque volume measurements expressed in mm3. In studies that tested drugs that did not affect lipids, only the placebo and control arms were used. In these circumstances, we did not consider the active arm due to potential bias related with extra-lipid mechanisms that could affect plaque regression. Mean values were considered for this analysis.

The quality of the studies was assessed with the Jadad scale. Potential publication biases were assessed with the Begg’s test.

Changes in lipid measurements (LDL-C, non-HDL-C, ApoB, and HDL-C) between baseline and end of follow-up were calculated and expressed in percentages and absolute values (mg/dL). We collected data from the control, placebo, and intervention arms in studies that compared the effect of different lipid-lowering treatments, and only from the placebo and control arms in studies that tested drugs that do not modify lipid levels. Baseline and final measurements of the CPV (expressed in mm3) were extracted and the percent changes were calculated using the formula: CPV Completion of Study - CPV Baseline/ CPV Baseline x 100.

Several linear regression analyses were performed. In the first model, we analyzed the relationship between percentage changes in LDL-C, non-HDL-C, and ApoB and percentage changes in CPV, comparing the baseline and final measurements in the same arm. These associations were adjusted for treatment time. In the second analysis, we assessed the relationship between absolute differences in lipid levels and percentage differences in CPV. For this analysis we calculated the absolute differences of the changes in lipid levels and the percentage differences of the variation in CPV measurements (follow-up - baseline values) between the intervention and control or placebo arms. Finally, we explored the association between LDL-C, non-HDL-C, and ApoB levels achieved at the end of follow-up (goal) and the percentage changes in CPV. To analyze the correlation, we used Pearson’s correlation coefficient. To interpret the data within a clinical context, we tested associations between LDL-C, non-HDL-C, and ApoB levels below the goals recommended by most current guidelines and changes in CVP (< 70, < 100, and < 80 mg/dL, respectively).

Data analysis was performed using Stata 11.1 and Epidat 3.1. All statistical tests were two sided and the statistical significance level alpha was set at 0.05 for the analysis.

 Results

Two independent authors searched the literature looking for studies compatible with the mentioned criteria. Of the 745 potential citations, 52 studies that evaluated any therapy on the regression of coronary plaque measured by IVUS were selected. Twenty-five studies were excluded due to the following main causes: absence of lipid values at the end of follow-up, quantification of plaque regression by another method, follow-up limitations, assessment of drugs not affecting lipids, or absence of a control/placebo arm. Most studies were randomized (77%) and two-thirds of them showed acceptable quality (3 or more points on the Jadad scale). We analyzed and discarded publication bias using the Begg's test (p = 0.55). Since not all studies reported ApoB values, more patients were included in the LDL-C and non-HDL-C analyses (4685) compared with the ApoB analysis (3065). A flow diagram of the study’s screening process is shown in Figure 1. Most studies included patients with stable coronary heart disease. Two studies included patients with acute coronary syndromes, one study included individuals with diabetes and another included subjects with metabolic syndrome. In studies involving patients with acute ischemic syndromes, IVUS measurement in the target segment was determined in a non-percutaneous coronary angioplasty site.

Flow diagram of the study screening process

Follow-up ranged from 3 to 24 months. The main characteristics of the 27 studies selected are shown in Table 1.

Studies included in the analysis (n = 4685)
Study Intervention (mg/day) n Change in LDL-C (%) Change in non- HDL-C (%) Change in ApoB (%) Change in coronary plaque volume (%) Months of treatment exposure
REVERSAL10 Atorvastatin 80 253 -46.3 -42.9 -39.1 -0.4 18
REVERSAL10 Pravastatin 40 249 -25.2 -24.7 -22 2.7 18
ESTABLISH11 Atorvastatin 20 35 -41.7 -35.4 -27.9 -13.1 6
ESTABLISH11 Control 35 -0.7 -1.9 2.4 8.7 6
JAPAN-ACS12 Pitavastatin 4 125 -36.2 -30.5 -27.6 -16.9 8-12
JAPAN-ACS12 Atorvastatin 20 127 -35.8 -30.1 -27.6 -18.1 8-12
SATURN13 Atorvastatin 80 519 -41.5 -35.9 -28.4 -4.0 26
SATURN13 Rosuvastatin 40 520 -47.8 -40.2 -30.9 -5.8 26
Hong et al.14 Rosuvastatin 20 65 -49 -44 -36 -2.7 11
Hong et al.14 Atorvastatin 40 63 -40 -35.4 -34 -1.9 11
COSMOS15 Rosuvastatin 2,5-20 215 -38.6 -36.7 -31.3 -5.1 19
ASTEROID6 Rosuvastatin 40 346 -53.2 -47.2 -41.5 -6.7 24
ARTMAP16 Atorvastatin 10-20 143 -47 -43.4 - -3.9 6
ARTMAP16 Rosuvastatin 20 128 -49 -45.9 - -7.4 6
GAIN17 Atorvastatin 20-80 65 -42 -41 - 2.5 12
GAIN17 Usual care 66 -16 -15.9 - 11.8 12
Kawasaki et al.18 Control 17 -1.9 -1.1 - 0 6
Kawasaki et al.18 Pravastatin 20 17 -31.5 -28.6 - -0.9 6
Kawasaki et al.18 Atorvastatin 20 18 -38.7 -39.2 - -2.4 6
Jensen et al.19 Simvastatin 40 40 -46.3 -42.8 - -6.3 3-12
Jensen et al.19 Diet 40 -2.4 -2.1 - -0.4 3-12
Han et al.20 Rosuvastatin 20 21 -54.2 -44.6 - -8.5 9-12
Han et al.20 Rosuvastatin 20/Ramipril 10 19 -47.2 -43.6 - -11.6 9-12
STRADIVARIUS21 Placebo 341 -3.2 -3.8 0.5 18
A-PLUS22 Placebo 154 1.7 1.9 -4 -1.2 24
AQUARIUS23 Placebo 233 5.6 4.4 - -1.1 26
Tani et al.24 Pravastatin 10-20 84 -11.3 -12.1 -6.4 -12.6 6
Nozue et al.25 Pitavastatin 4 58 -41 -37.9 -33 -2.2 8
Nozue et al.25 Pravastatin 20 61 -29 -26.4 -25.2 -1.4 8
Hirayama et al.26 Atorvastatin 10-20 20 -36.3 -36.4 -28.4 -18.9 20
HEAVEN 27 Atorvastatin 80/Ezetimibe 10 42 -28.6 -32.3 -5.8 -2.9 12
HEAVEN27 Standard treatment 47 -1.9 -9.2 7.4 0.7 12
CART-228 Placebo 111 -6.9 -8.4 - -0.3 12
ENCORE II29 Placebo 112 -11.8 -9.8 - -0.3 18-24
Nasu et al.30 Fluvastatin 40 40 -32.3 -32.8 -27 -8.3 12
Nasu et al.30 Control 39 2.2 4 2.3 2.5 12
Yamada et al.31 Atorvastatin 10-20 26 -32.5 -29.8 -27.6 -1.9 12
Yamada et al.31 Usual care 32 0 -1.6 -2.2 11.5 12
Tani et al.32 Pravastatin 10-20 52 -14 -17.9 - -14 6
Tani et al.32 Control 23 3.6 2.5 - 1.1 6
Yokoyama et al.33 Atorvastatin 10 29 -34 -30.5 - -5.6 6
Yokoyama et al.33 Control 30 -4.4 -5.2 - -3.5 6
Nakayama et al.34 Control 25 -7.1 -4.6 - 2.8 6

Correlations between percentage changes in LDL-C, non-HDL-C, and ApoB with percentage changes in CPV were moderate (r = 0.47, p = 0.0013; r = 0.46, p = 0.0016; and r = 0.43, p = 0.03, respectively), whereas correlations between absolute differences in LDL-C, non-HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, p = 0.015; r = 0.52, p = 0.03; and r = 0.80, p = 0.017, respectively). Similarly, the correlation between LDL-C / HDL-C ratio and regression of atherosclerosis was moderate (r = 0.47, p = 0.001). However, the correlation between HDL-C and percentage changes in CPV was poor (r = 0.24, p = 0.08).

The linear regression model showed a significant association between percentage changes in LDL-C (p = 0.002), non-HDL-C (p = 0.002), and ApoB (p = 0.04) with percentage changes in CPV (Figures 2, 3, and 4). These associations remained significant even after adjustment for treatment time (p = 0.006, p = 0.002 and p = 0.035 for LDL-C, non-HDL-C, and ApoB, respectively). Also, a significant association between percentage changes in LDL-C / HDL-C ratio with percentage changes in CPV (p = 0.002) was demonstrated, but not with changes in HDL-C (p = 0.09). Similarly, significant associations were found between absolute reductions in LDL-C (p = 0.02), non-HDL-C (p = 0.03), and ApoB (p = 0.02) with percentage differences in CPV changes between groups. Figure 5 illustrates the association between the absolute reduction in ApoB and the percentage regression in CPV.

Relationship between changes in LDL-C plasma levels and variation in coronary plaque volume Relationship between changes in non-HDL-C plasma levels and variation in coronary plaque volume Relationship between changes in apolipoprotein B plasma levels and variation in coronary plaque volume Relationship between the absolute difference in apolipoprotein B plasma levels and the percentage difference of the variation in coronary plaque volume

The correlation between the LDL-C goal and percentage change in CPV was moderate (r = 0.48, p = 0.01). However, this association was significant and continuous up to LDL-C levels close to 50 mg/dL (Figure 6). Similarly, the correlation between the non-HDL-C goal and percentage change in CPV was significant (p = 0.01) and continuous up to non-HDL-C levels close to 80 mg/dL. Finally, we found an almost significant association (p = 0.056) between ApoB goal and percentage change in CPV in values close to 60 mg/dL.

Relationship between LDL-C levels achieved at the end of the follow-up (LDL-C goal) and percentage changes in coronary plaque volume

In a combined analysis of all treatment types, a 10% decrease in LDL-C, non-HDL-C, or ApoB was associated, respectively, with 2.7%, 2.9%, and 3% regressions in CPV.

 Discussion

The regression of atherosclerosis is a surrogate of cardiovascular disease, and has been evaluated in research studies mainly by IVUS and carotid ultrasound. However, the independent predictive value of these methods is not similar. A recent meta-analysis found no significant association between LDL-C reduction and progression of atherosclerosis estimated by carotid intima-media thickness35. Furthermore, regression or slowed progression of carotid intima-media thickness induced by cardiovascular drug therapies do not reflect reductions in cardiovascular events36.

In contrast, analyses that have included only a few studies have shown a significant association between LDL-C reduction and regression of coronary plaque measured by IVUS3 , 4. Also, the association between the regression of coronary atherosclerotic plaque measured by IVUS and the incidence of non-fatal cardiovascular events has been demostrated5. In our study, IVUS was chosen as the most robust method to detect plaque regression, and this was the first time that plasma levels of non HDL-C and ApoB were added to the analysis.

Large body of evidence supports a central role for LDL-C lowering in the prevention of atherosclerotic cardiovascular disease. However, the new guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults discourages the use of absolute values of LDL-C as a “goal” and makes virtually no reference to other markers more specific of atherogenic lipid particles, such as non-HDL-C or ApoB37.

In our study, we found no threshold level of lipid reduction (absolute or percentage) associated with an interruption in plaque regression, suggesting that lower levels of atherogenic particles are associated with greater regression of plaque. In our analysis, we observed a significant, sustained, and continuous association between LDL-C, non-HDL-C, and ApoB levels at the end of follow-up with changes in CPV, suggesting that the respective goals of < 70, < 100, and < 80 mg/dL recommended by most guidelines is appropriate.38 , 39This finding does not conceptually agree with the latest guideline, which recommends that an approximate 50% reduction in LDL-C level is adequate regardless of the LDL-C goal achieved40.

Another interesting finding to emphasize is that the regression of atherosclerosis in our study was independent of the lipid-lowering therapy (statins) and the dose used. When significant reductions in LDL-C, non-HDL-C, or ApoB were achieved, plaque regression was observed with different doses of statins. This finding also contrasts with the new guideline that recommends only intensive doses of rosuvastatin or atorvastatin. Finally, the significant association between the LDL-C / HDL-C ratio and regression of atherosclerosis indicates the importance of a balance between pro- and anti-atherogenic particles on vascular remodeling.

Correlations between the percentage reduction in different lipid markers and the CPV regression in our study were moderate, suggesting that the progression/regression of coronary atherosclerosis is multicausal. The correlation between the absolute change in ApoB and the percentage variation in plaque volume was higher, although this result emerges with the inclusion of a very small number of studies. This finding is consistent with the concept that ApoB level could be a better predictor of cardiovascular events than the LDL-C level, since it reflects more accurately the number of atherogenic particles9.

Study limitations

Like all analyses of secondary data, there are many limitations related to the heterogeneity of the populations included, number of subjects analyzed and variability of follow-up. We found heterogeneity when we analyzed the L’Abbé and Galbraith plots, but not all studies could be analyzed, since the data required for the analysis were not always published. We understand that whereas there may be “statistical heterogeneity”, we have not seen a marked clinical heterogeneity. Then, the fundamental objective of our work was to show the linear relationship between the changes in lipid levels and regression of atherosclerotic plaque, and not force a summary measure.

In previous analysis, C-reactive protein level was an important determinant of plaque regression. Our study did not analyze this biomarker. Also, the percentage atheroma volume (PAV) is a more stable measurement of the coronary plaque than the total atheroma volume. However, we decided to choose the percentage change in total atheroma volume as the end point because the PAV was only reported in 15 of the 27 studies included in this analysis. Finally, this analysis was performed with data imported from the studies and not with individual patient data; therefore, the results are not entirely accurate.

 Conclusion

We found in our analysis significant associations between changes in LDL-C, non-HDL-C, and ApoB levels and regression of coronary plaque measured by IVUS. These results are aligned with the concept “lower LDL-C is better” and expand this assumption to other atherogenic lipid markers.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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Effects of the acyl coenzyme A: cholesterolacyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation. 2004;110(21):3372-7. Tardif JC Grégoire J L'Allier PL.Anderson TJ.Bertrand O.Reeves FAvasimibe and Progression of Lesions on UltraSound Investigators Effects of the acyl coenzyme A: cholesterolacyltransferase inhibitor avasimibe on human atherosclerotic lesions Circulation 2004 110 21 3372 3377 Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, Armbrecht J, et al. Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. JAMA. 2013;310(11):1135-44. Nicholls SJ Bakris GL Kastelein JJ Menon V Williams B Armbrecht J Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial JAMA 2013 310 11 1135 1144 Tani S, Nagao K, Anazawa T, Kawamata H, Furuya S, Takahashi H, et al. Coronary plaque regression and lifestyle modification in patients treated with pravastatin. Assessment mainly by daily aerobic exercise and an increase in the serum level of high-density lipoprotein cholesterol. Circ J. 2010;74(5):954-61. Tani S Nagao K Anazawa T Kawamata H Furuya S Takahashi H Coronary plaque regression and lifestyle modification in patients treated with pravastatin. Assessment mainly by daily aerobic exercise and an increase in the serum level of high-density lipoprotein cholesterol Circ J 2010 74 5 954 961 Nozue T, Yamamoto S, Tohyama S, Umezawa S, Kunishima T, Sato A, et al. Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis. Am Heart J. 2012;163(2):191-9. Nozue T Yamamoto S Tohyama S Umezawa S Kunishima T Sato A Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis Am Heart J 2012 163 2 191 199 Hirayama A, Saito S, Ueda Y, Takayama T, Honye J, Komatsu S, et al. Qualitative and quantitative changes in coronary plaque associated with atorvastatin therapy. Circ J. 2009;73(4):718-25. Hirayama A Saito S Ueda Y Takayama T Honye J Komatsu S Qualitative and quantitative changes in coronary plaque associated with atorvastatin therapy Circ J 2009 73 4 718 725 Kovarnik T, Mintz GS, Skalicka H, Kral A, Horak J, Skulec R, et al. Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration: HEAVEN study. Circ J. 2012;76(1):176-83. Kovarnik T Mintz GS Skalicka H Kral A Horak J Skulec R Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration: HEAVEN study Circ J 2012 76 1 176 183 Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Anderson TJ, Reeves F, et al; CART-2 Investigators. Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial. Atherosclerosis. 2008;197(1):480-6. Tardif JC Grégoire J L'Allier PL Ibrahim R Anderson TJ Reeves F CART-2 Investigators Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial Atherosclerosis 2008 197 1 480 486 Lüscher TF, Pieper M, Tendera M, Vrolix M, Rutsch W, van den Branden F, et al. Randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study. Eur Heart J. 2009;30(13):1590-7. Lüscher TF Pieper M Tendera M Vrolix M Rutsch W van den Branden F Randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study Eur Heart J 2009 30 13 1590 1597 Nasu K, Tsuchikane E, Katoh O, Tanaka N, Kimura M, Ehara M, et al. Effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by virtual histology intravascular ultrasound. JACC Cardiovasc Interv. 2009;2(7):689-96. Nasu K Tsuchikane E Katoh O Tanaka N Kimura M Ehara M Effect of fluvastatin on progression of coronary atherosclerotic plaque evaluated by virtual histology intravascular ultrasound JACC Cardiovasc Interv 2009 2 7 689 696 Yamada T, Azuma A, Sasaki S, Sawada T, Matsubara H; REACH Study Group. Randomized evaluation of atorvastatin in patients with coronary heart disease: a serial intravascular ultrasound study. Circ J. 2007;71(12):1845-50. Yamada T Azuma A Sasaki S Sawada T Matsubara H REACH Study Group Randomized evaluation of atorvastatin in patients with coronary heart disease: a serial intravascular ultrasound study Circ J 2007 71 12 1845 1850 Tani S, Watanabe I, Anazawa T, Kawamata H, Tachibana E, Furukawa K, et al; Surugadai Atherosclerosis Regression Investigators. Effect of pravastatin on malondialdehyde-modified low-density lipoprotein levels and coronary plaque regression as determined by three-dimensional intravascular ultrasound. Am J Cardiol. 2005;96(8):1089-94. Tani S Watanabe I Anazawa T Kawamata H Tachibana E Furukawa K Surugadai Atherosclerosis Regression Investigators Effect of pravastatin on malondialdehyde-modified low-density lipoprotein levels and coronary plaque regression as determined by three-dimensional intravascular ultrasound Am J Cardiol 2005 96 8 1089 1094 Yokoyama M, Komiyama N, Courtney BK, Nakayama T, Namikawa S, Kuriyama N, et al. Plasma low-density lipoprotein reduction and structural effects on coronary atherosclerotic plaques by atorvastatin as clinically assessed with intravascular ultrasound radio-frequency signal analysis: a randomized prospective study. Am Heart J. 2005;150(2):287. Yokoyama M Komiyama N Courtney BK Nakayama T Namikawa S Kuriyama N Plasma low-density lipoprotein reduction and structural effects on coronary atherosclerotic plaques by atorvastatin as clinically assessed with intravascular ultrasound radio-frequency signal analysis: a randomized prospective study Am Heart J 2005 150 2 287 287 Nakayama T, Komiyama N, Yokoyama M, Namikawa S, Kuroda N, Kobayashi Y, et al. Pioglitazone induces regression of coronary atherosclerotic plaques in patients with type 2 diabetes mellitus or impaired glucose tolerance: a randomized prospective study using intravascular ultrasound. Int J Cardiol. 2010;138(2):157-65. Nakayama T Komiyama N Yokoyama M Namikawa S Kuroda N Kobayashi Y Pioglitazone induces regression of coronary atherosclerotic plaques in patients with type 2 diabetes mellitus or impaired glucose tolerance: a randomized prospective study using intravascular ultrasound Int J Cardiol 2010 138 2 157 165 Huang Y, Li W, Dong L, Li R, Wu Y. Effect of statin therapy on the progression of common carotid artery intima-media thickness: an updated systematic review and meta-analysis of randomized controlled trials. J Atheroscler Thromb. 2013;20(1):108-21. Huang Y Li W Dong L Li R Wu Y Effect of statin therapy on the progression of common carotid artery intima-media thickness: an updated systematic review and meta-analysis of randomized controlled trials J Atheroscler Thromb 2013 20 1 108 121 Costanzo P, Perrone-Filardi P, Vassallo E, Paolillo S, Cesarano P, Brevetti G, et al. Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials. J Am Coll Cardiol. 2010;56(24):2006-20. Costanzo P Perrone-Filardi P Vassallo E Paolillo S Cesarano P Brevetti G Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials J Am Coll Cardiol 2010 56 24 2006 2020 Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63 (25 Pt B):2889-934. Stone NJ Robinson JG Lichtenstein AH Bairey Merz CN Blum CB Eckel RH ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2014 63 25 Pt B 2889 2934 Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32(14):1769-818. Reiner Z Catapano AL De Backer G Graham I Taskinen MR Wiklund O ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Eur Heart J 2011 32 14 1769 1818 Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012 Update of the Canadian Cardiovascular Society Guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013;29(2):151-67. Anderson TJ Grégoire J Hegele RA Couture P Mancini GB McPherson R 2012 Update of the Canadian Cardiovascular Society Guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult Can J Cardiol 2013 29 2 151 167 Ray KK, Kastelein JJ, Boekholdt SM, Nicholls SJ, Khaw KT, Ballantyne CM, et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J. 2014;35(15):960-8. Ray KK Kastelein JJ Boekholdt SM Nicholls SJ Khaw KT Ballantyne CM The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011 Eur Heart J 2014 35 15 960 968 Associação entre Níveis De LDL-C, Não-HDL-C E Apolipoproteína B com Regressão de Placa Coronariana Masson Walter 1 2 Siniawski Daniel 1 2 Lobo Martín 1 Molinero Graciela 1 Giorgi Mariano 1 Huerín Melina 1 Consejo de Epidemiología y Prevención Cardiovascular de la Sociedad Argentina de Cardiología Buenos Aires Argentina Consejo de Epidemiología y Prevención Cardiovascular de la Sociedad Argentina de Cardiología, Buenos Aires - Argentina Hospital Italiano de Buenos Aires Buenos Aires Argentina Hospital Italiano de Buenos Aires, Buenos Aires - Argentina Universidad de Buenos Aires Correspondência: Walter Masson, Hospita Italiano de Buenos Aires. Gascon 450, Ciudad Autónoma de Buenos Aires. Postal Code 1416, Buenos Aires – Argentina. E-mail: walter.masson@hospitalitaliano.org.ar

Contribuição dos autores

Concepção e desenho da pesquisa: Masson W, Siniawski D, Huerín M. Obtenção de dados: Masson W, Lobo M, Molinero G, Huerín M. Análise e interpretação dos dados: Masson W, Siniawski D, Lobo M, Giorgi M, Huerín M. Análise estatística: Masson W, Lobo M. Redação do manuscrito: Masson W, Siniawski D, Molinero G, Huerín M. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Masson W, Siniawski D, Lobo M, Molinero G, Giorgi M, Huerín M. Supervisão / como investigador principal: Masson W.

Potencial Conflito de Interesse

Dr. Giorgi relatou ter recebido uma bolsa educacional da Pfizer e da BMS

 Fundamento:

Estudos prévios sugerem uma relação linear entre o LDL-C e mudanças no volume de placa coronariana (VPC) medido por ultrassonografia intravascular. No entanto, estas publicações incluíram um número pequeno de estudos e não exploraram outros marcadores lipídicos.

 Objetivo:

Avaliar a associação entre alterações nos marcadores lipídicos e regressão no VPC com base em dados publicados.

 Métodos:

Nós coletamos dados dos braços controle, placebo e intervenção de estudos que compararam o efeito de tratamentos hipolipemiantes no VPC, e dos braços placebo e controle de estudos que testaram medicamentos que não afetam os lipídios. Os volumes inicial e final da placa, representados em mm3, foram extraídos e as alterações percentuais após as intervenções foram calculadas. Nós realizamos três análises de regressão linear e avaliamos a relação entre alterações percentuais e absolutas dos marcadores lipídicos com as variações percentuais do VPC.

 Resultados:

Vinte e sete estudos foram selecionados. As correlações entre as variações percentuais do LDL-C, não- HDL-C e apolipoproteína B (ApoB) com variações percentuais do VPC foram moderadas (r = 0,48; r = 0,47; e r = 0,44, respectivamente). As correlações entre diferenças absolutas do LDL-C, não-HDL-C e ApoB com diferenças percentuais do VPC foram mais fortes (r = 0,57; r = 0,52; e r = 0,79). O modelo de regressão linear mostrou uma associação estatisticamente significativa entre a redução nos marcadores lipídicos e regressão no volume da placa.

 Conclusão:

Observamos uma associação significativa entre alterações de diferentes partículas aterogênicas e regressão do VPC. A redução absoluta da ApoB mostrou a correlação mais forte com a regressão da placa coronariana.

 Doenças Cardiovasculares Aterosclerose/fisiopatologia LDL-Colesterol Apolipoproteína B/uso terapêutico Lipoproteínas LDL Introdução

Nos últimos vinte anos, fortes evidências de estudos clínicos demonstraram que a redução do colesterol da lipoproteína de baixa densidade (LDL-C) com diferentes medicamentos hipolipemiantes, principalmente os inibidores da HMG-CoA redutase (estatinas), é fundamental para diminuir a incidência de eventos coronarianos1 , 2. Da mesma forma, estudos diversos mostraram uma associação entre a redução do LDL-C e regressão da placa coronariana medida por ultrassonografia intravascular (USIV)3 , 4. Um estudo recente de meta-regressão mostrou que a regressão farmacológica da carga de placa aterosclerótica está associada a uma redução clinicamente significativa de infarto do miocárdio e revascularização5.

Estudos prévios sugerem uma associação linear entre o LDL-C e variações no volume de placa aterosclerótica coronariana (VPC) avaliado por USIV6 , 7. No entanto, estas publicações incluíram um número pequeno de estudos e não exploraram a relação com outros marcadores lipídicos, como o colesterol não lipoproteína de alta densidade (não-HDL-C) e a apolipoproteína B (ApoB), que em vários estudos foram relacionados com mais proximidade ao risco de doença vascular do que o próprio LDL-C8 , 9.

Neste contexto, o objetivo deste estudo foi avaliar a associação entre alterações nos níveis plasmáticos de marcadores lipídicos (LDL-C, não-HDL-C e ApoB) e regressão da placa coronariana medida por USIV com base em dados publicados.

 Métodos

Dois revisores fizeram uma busca independente nos bancos de dados eletrônicos PubMed/Medline, EMBASE e Cochrane Clinical Trials com os seguintes termos: "Ultrassonografia intravascular", "USIV", "regressão da aterosclerose" e "estatinas". Os estudos foram selecionados de acordo com os seguintes critérios: a) ensaios que exploraram o efeito de um ou mais medicamentos hipolipemiantes distintos (ou em dosagens diferentes) na variação do VPC avaliado por USIV (volume total do ateroma), b) pelo menos três meses de acompanhamento e c) disponibilidade de medidas do volume de placa representadas em mm3. Em estudos que testaram medicamentos que não afetam os lipídios, foram considerados apenas os braços placebo e controle. Nestas circunstâncias, nós não consideramos o braço ativo devido a um potencial viés relacionado com mecanismos extra-lipídicos que poderiam afetar a regressão da placa. Para esta análise, foi considerada a média dos valores.

A qualidade dos estudos foi avaliada com a escala de Jadad. Potenciais vieses de publicação foram avaliados com o teste de Begg.

As alterações nas medidas dos lipídios (LDL-C, não-HDL-C, ApoB e HDL-C) entre o início e o final do acompanhamento foram calculadas e representadas em porcentagens e valores absolutos (mg/dL). Nós coletamos dados dos braços controle, placebo e intervenção em estudos que compararam o efeito de diferentes tratamentos hipolipemiantes, e somente dos braços placebo e controle em estudos que testaram drogas que não modificam os níveis lipídicos. Medidas iniciais e finais do VPC (representadas em mm3 ) foram extraídas e as mudanças percentuais foram calculadas com a fórmula: VPC na Conclusão do Estudo - VPC Inicial / VPC Inicial x 100.

Nós realizamos várias análises de regressão linear. No primeiro modelo, analisamos a relação entre as mudanças percentuais do LDL-C, não-HDL-C e ApoB com as mudanças percentuais do VPC, comparando as medidas iniciais e finais no mesmo braço. Estas associações foram ajustadas de acordo com o tempo de tratamento. Na segunda análise, nós avaliamos a relação entre diferenças absolutas nos níveis lipídicos e diferenças percentuais no VPC. Para esta análise, nós calculamos as diferenças absolutas das mudanças nos níveis de lipídios e as diferenças percentuais na variação das medidas de VPC (valores finais - valores iniciais) entre os braços de intervenção e controle ou placebo. Por fim, nós exploramos a associação entre os níveis de LDL-C, não-HDL-C e ApoB ao final do seguimento (meta) e as alterações percentuais do VPC. Para analisar a correlação, nós utilizamos o coeficiente de correlação de Pearson. Para interpretar os dados em um contexto clínico, nós testamos associações entre os níveis de LDL-C, não-HDL-C e ApoB abaixo das metas recomendadas pelas diretrizes mais recentes e mudanças no VPC (< 70, < 100 e < 80 mg/dL, respectivamente).

A análise dos dados foi realizada com os programas Stata 11.1 e Epidat 3.1. Todos os testes estatísticos foram bicaudais e o nível alfa de significância estatística foi fixado em 0,05 para a análise.

 Resultados

Dois autores pesquisaram a literatura independentemente à procura de estudos compatíveis com os critérios mencionados. De 745 citações potenciais, foram selecionados 52 estudos que avaliaram terapias de qualquer tipo na regressão da placa coronariana medida por USIV. Vinte e cinco estudos foram excluídos pelos seguintes motivos principais: ausência de valores de lipídios ao final do acompanhamento, quantificação da regressão da placa por outro método, limitações no seguimento, avaliação de medicamentos que não afetam lipídios, ou ausência de braço controle/placebo. Os estudos eram randomizados na sua maioria (77%) e dois terços deles mostraram qualidade aceitável (3 ou mais pontos na escala de Jadad). Nós analisamos e descartamos vieses de publicação com o teste de Begg (p = 0,55). Uma vez que nem todos os estudos relataram os níveis de ApoB, foram incluídos mais pacientes na análise do LDL-C e não-HDL-C (4.685) do que na análise da ApoB (3.065). A Figura 1 apresenta um diagrama de fluxo do processo de triagem dos estudos. A maioria dos estudos incluiu pacientes com doença coronariana estável. Dois estudos incluíram pacientes com síndromes coronarianas agudas, um estudo incluiu indivíduos com diabetes e outro com síndrome metabólica. Em estudos envolvendo pacientes com síndromes isquêmicas agudas, a medida por USIV do segmento-alvo foi determinada em um local diferente do local da intervenção coronariana percutânea.

Diagrama de fluxo do processo de triagem dos estudos.

O acompanhamento variou entre 3 e 24 meses. As características principais dos 27 estudos selecionados estão mostradas na Tabela 1.

Estudos incluídos na análise (n = 4.685)
Estudo Intervenção (mg/dia) n Alteração no LDL-C (%) Alteração no não-HDL-C (%) Alteração na ApoB (%) Mudança no volume de placa coronariana (%) Meses de exposição ao tratamento
REVERSAL 10 Atorvastatlna 80 253 -46,3 -42,9 -39,1 -0,4 18
REVERSAL 10 Pravastatlna 40 249 -25,2 -24,7 -22 2,7 18
ESTABLISH 11 Atorvastatlna 20 35 -41,7 -35,4 -27,9 -13,1 6
ESTABLISH 11 Controle 35 -0,7 -1,9 2,4 8,7 6
JAPAN-ACS 12 Pitavastatina 4 125 -36,2 -30,5 -27,6 -16,9 8-12
JAPAN-ACS 12 Atorvastatlna 20 127 -35,8 -30,1 -27,6 -18,1 8-12
SATURN 13 Atorvastatlna 80 519 -41,5 -35,9 -28,4 -4,0 26
SATURN 13 Rosuvastatlna 40 520 -47,8 -40,2 -30,9 -5,8 26
Hong et al. 14 Rosuvastatlna 20 65 -49 -44 -36 -2,7 11
Hong et al. 14 Atorvastatlna 40 63 -40 -35,4 -34 -1,9 11
COSMOS 15 Rosuvastatlna 2,5-20 215 -38,6 -36,7 -31,3 -5,1 19
ASTEROID 6 Rosuvastatlna 40 346 -53,2 -47,2 -41,5 -6,7 24
ARTMAP 16 Atorvastatlna 10-20 143 -47 -43,4 - -3,9 6
ARTMAP 16 Rosuvastatlna 20 128 -49 -45,9 - -7,4 6
GAIN 17 Atorvastatlna 20-80 65 -42 -41 - 2,5 12
GAIN 17 Tratamento habltual 66 -16 -15,9 - 11,8 12
Kawasaki e cols. 18 Controle 17 -1,9 -1,1 - 0 6
Kawasaki e cols. 18 Pravastatlna 20 17 -31,5 -28,6 - -0,9 6
Kawasaki e cols. 18 Atorvastatlna 20 18 -38,7 -39,2 - -2,4 6
Jensen e cols. 19 Slnvastatlna 40 40 -46,3 -42,8 - -6,3 3-12
Jensen e cols. 19 Dleta 40 -2,4 -2,1 - -0,4 3-12
Han e cols. 20 Rosuvastatlna 20 21 -54,2 -44,6 - -8,5 9-12
Han e cols. 20 Rosuvastatlna 20/Ramlprll 10 19 -47,2 -43,6 - -11,6 9-12
STRADIVARIUS 21 Placebo 341 -3,2 -3,8 0,5 18
A-PLUS 22 Placebo 154 1,7 1,9 -4 -1,2 24
AQUARIUS 23 Placebo 233 5,6 4,4 - -1,1 26
Tani e cols. 24 Pravastatlna 10-20 84 -11,3 -12,1 -6,4 -12,6 6
Nozue e cols. 25 Pltavastatlna 4 58 -41 -37,9 -33 -2,2 8
Nozue e cols. 25 Pravastatlna 20 61 -29 -26,4 -25,2 -1,4 8
Hirayama e cols. 26 Atorvastatlna 10-20 20 -36,3 -36,4 -28,4 -18,9 20
HEAVEN 27 Atorvastatlna 80/Ezetlmlba 10 42 -28,6 -32,3 -5,8 -2,9 12
HEAVEN 27 Tratamento padrão 47 -1,9 -9,2 7,4 0,7 12
CART-2 28 Placebo 111 -6,9 -8,4 - -0,3 12
ENCORE II 29 Placebo 112 -11,8 -9,8 - -0,3 18-24
Nasu e cols. 30 Fluvastatlna 40 40 -32,3 -32,8 -27 -8,3 12
Nasu e cols. 30 Controle 39 2,2 4 2,3 2,5 12
Yamada e cols. 31 Atorvastatlna 10-20 26 -32,5 -29,8 -27,6 -1,9 12
Yamada e cols. 31 Tratamento habltual 32 0 -1,6 -2,2 11,5 12
Tani e cols. 32 Pravastatlna 10-20 52 -14 -17,9 - -14 6
Tani e cols. 32 Controle 23 3,6 2,5 - 1,1 6
Yokoyama e cols. 33 Atorvastatlna 10 29 -34 -30,5 - -5,6 6
Yokoyama e cols. 33 Controle 30 -4,4 -5,2 - -3,5 6
Nakayama e cols. 34 Controle 25 -7,1 -4,6 - 2,8 6

As correlações entre variações percentuais do LDL-C, não-HDL-C e ApoB com alterações percentuais do VPC foram moderadas (r = 0,47 e p = 0,0013; r = 0,46 e p = 0,0016; r = 0,43 e p = 0,03, respectivamente), ao passo que as correlações entre diferenças absolutas do LDL-C, não-HDL-C e ApoB com diferenças percentuais do VPC foram mais fortes (r = 0,57 e p = 0,015; r = 0,52 e p = 0,03; e r = 0,80 e p = 0,017, respectivamente). Da mesma forma, a correlação entre a razão LDL / HDL e regressão da aterosclerose foi moderada (r = 0,47; p = 0,001). No entanto, a correlação entre as mudanças percentuais de HDL-C com mudanças percentuais de VPC foi pobre (r = 0,24; p = 0,08).

O modelo de regressão linear mostrou uma associação significativa entre as alterações percentuais do LDL-C (p = 0,002), não-HDL-C (p = 0,002) e ApoB (p = 0,04) com variações percentuais no VPC (Figuras 2, 3 e 4). Essas associações permaneceram significativas mesmo após ajuste por tempo de tratamento (p = 0,006; p = 0,002; e p = 0,035 para o LDL-C, não-HDL-C e ApoB, respectivamente). Foi demonstrada também uma associação significativa entre variações percentuais nas mudanças da razão LDL-C / HDL-C com mudanças percentuais do VPC (p = 0,002), mas não com mudanças no HDL-C (p = 0,09). Da mesma forma, foram encontradas associações significativas entre as reduções absolutas do LDL-C (p = 0,02), não-HDL-C (p = 0,03) e ApoB (p = 0,02) com as diferenças percentuais do VPC entre os grupos. A Figura 5 mostra a associação entre a redução absoluta da ApoB e a regressão percentual do VPC.

Relação entre alterações nos níveis plasmáticos de LDL-C e variação no volume de placa coronariana. Relação entre alterações nos níveis plasmáticos de não-HDL-C e variação no volume de placa coronariana. Relação entre alterações nos níveis plasmáticos de apolipoproteína B e variação no volume de placa coronariana. Relação entre a diferença absoluta nos níveis plasmáticos de apolipoproteína B e a diferença percentual da variação no volume de placa coronariana.

A correlação entre a meta do LDL-C e a mudança percentual do VPC foi moderada (r = 0,48; p = 0,01). No entanto, essa associação foi significativa e contínua até níveis de LDL-C próximos a 50 mg/dL (Figura 6). Da mesma forma, a correlação entre a meta do não-HDL-C e a variação percentual do VPC foi significativa (p = 0,01) e contínua até níveis de não-HDL-C próximos a 80 mg/dL. Por fim, encontramos uma associação quase significativa (p = 0,056) entre a meta da ApoB com a mudança percentual no VPC em valores próximos a 60 mg/dL. Em uma análise combinada de todos os tipos de tratamento, uma redução de 10% no LDL-C, não-HDL-C ou ApoB esteve associada com regressões no VPC de 2,7%, 2,9% e 3%, respectivamente.

Relação entre os níveis de LDL-C alcançados ao final do acompanhamento (meta do LDL-C) e alterações no volume de placa coronariana. Discussão

A regressão da aterosclerose é uma substituta para a doença cardiovascular, e tem sido avaliada em estudos de investigação principalmente por USIV e ultrassonografia de carótidas. No entanto, o valor preditivo independente desses métodos não é semelhante. Uma metanálise recente não encontrou associação significativa entre a redução do LDL-C e progressão da aterosclerose estimada pela espessura das camadas íntima e média da carótida35. Além disso, a regressão ou diminuição na velocidade de progressão da espessura das camadas íntima e média induzida por terapias medicamentosas cardiovasculares não reflete reduções de eventos cardiovasculares36.

Por outro lado, as análises que incluem apenas alguns estudos mostraram uma associação significativa entre a redução do LDL-C e regressão da placa coronariana avaliada por USIV3 , 4. A associação entre a regressão da placa aterosclerótica coronariana medida por USIV e a incidência de eventos cardiovasculares não fatais também tem sido demonstrada5. Nós escolhemos a USIV em nosso estudo como o método mais robusto para detectar a regressão da placa e pela primeira vez, adicionamos à análise os níveis plasmáticos de não HDL-C e ApoB.

Várias evidências suportam um papel central para a redução do LDL-C na prevenção da doença cardiovascular aterosclerótica. No entanto, a nova diretriz sobre o tratamento do colesterol sanguíneo para reduzir o risco de aterosclerose cardiovascular em adultos desestimula o uso de valores absolutos de LDL-C como "meta" e não faz virtualmente nenhuma referência a outros marcadores mais específicos de partículas lipídicas aterogênicas, tais como o não-HDL-C ou a ApoB37.

Em nosso estudo, não encontramos nenhum nível limítrofe (absoluto ou percentual) de redução de lipídios associado a uma interrupção na regressão da placa, sugerindo que níveis mais baixos de partículas aterogênicas estariam associados com maior regressão da placa. Em nossa análise, observamos uma associação significativa, sustentada e contínua entre níveis de LDL-C, não-HDL-C e ApoB ao final do acompanhamento e mudanças no VPC, sugerindo que as metas de < 70, < 100 e < 80 mg/dL recomendadas pela maioria das diretrizes estariam apropriadas38 , 39. Essa constatação discorda conceitualmente da diretriz mais recente que recomenda que uma redução aproximada de 50% no nível do LDL-C estaria adequada independente de se atingir a meta para o LDL-C40.

Outro achado interessante que deve ser enfatizado é que a regressão da aterosclerose em nosso estudo foi independente da terapia hipolipemiante (estatinas) e da dose utilizada. Quando reduções significativas de LDL-C, não-HDL-C ou ApoB foram alcançadas, observamos regressão da placa com diferentes doses de estatinas. Esse achado também contrasta com a nova diretriz que recomenda apenas doses intensivas de rosuvastatina ou atorvastatina. Por fim, a associação significativa entre a razão LDL-C/HDL-C e regressão da aterosclerose indica a importância do equilíbrio entre partículas pró-aterogênicas e antiaterogênicas na remodelação vascular.

As correlações entre a porcentagem de redução de diferentes marcadores lipídicos e a regressão do VPC em nosso estudo foram moderadas, sugerindo que a progressão/regressão da aterosclerose coronariana é multicausal. A correlação entre a variação absoluta da ApoB e a variação percentual no volume da placa foi maior, embora esse resultado tenha surgido com a inclusão de um pequeno número de estudos. Essa constatação é consistente com o conceito de que o nível da ApoB poderia ser um melhor preditor de eventos cardiovasculares do que o nível do LDL-C, uma vez que reflete com maior precisão o número de partículas aterogênicas9.

Limitações do estudo

Como toda análise de dados secundários, existem várias limitações relacionadas à heterogeneidade das populações incluídas, número de indivíduos analisados e variabilidade no período de seguimento. Encontramos heterogeneidade quando analisamos os gráficos de L’Abbé e Galbraith, mas nem todos os estudos puderam ser analisados, uma vez que os dados necessários para essa análise nem sempre estavam publicados. Apesar de entendermos que possa ter ocorrido "heterogeneidade estatística", não observamos uma heterogeneidade clínica importante. Dentro disso, o objetivo fundamental do nosso trabalho foi mostrar a relação linear entre as mudanças nos níveis de lipídios e regressão de placa de ateroma sem forçar uma medida sumária.

Em uma análise anterior, o nível de proteína C reativa foi um determinante importante de regressão de placa. Nosso estudo não analisou esse biomarcador. Além disto, a porcentagem do volume do ateroma (PVA) é uma medida mais estável de placa coronariana do que o volume total do ateroma. No entanto, decidimos escolher a variação no percentual total do volume do ateroma como critério de avaliação, pois a PAV havia sido relatada em apenas 15 dos 27 estudos incluídos nesta análise. Por fim, essa análise foi realizada com dados obtidos a partir de estudos e não com dados individuais dos pacientes, portanto, os resultados não são completamente precisos.

 Conclusão

Encontramos em nossa análise associações significativas entre alterações do LDL-C, não-HDL-C e ApoB com regressão de placa coronariana medida por USIV. Esses resultados estão alinhados com o conceito de que "níveis mais baixos de LDL-C são melhores" e expandem essa suposição para outros marcadores lipídicos aterogênicos.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Não há vinculação deste estudo a programas de pós-graduação.