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Original Articles
NUMBER 1-2 YEAR 2011
A Clinical Study on the Efficacy of Statin Treatment Associated with the Control of Risk Factors of Atherosclerosis in Patients with Coronary Artery Disease
1 Department of Pharmacology,
2 Department of Microsurgery, Victor Babes University of Medicine and Pharmacy, Timisoara,
3 Department of Cardiology, Institute of Cardiovascular Disease, Timisoara

Correspondence to:
Beatrice Barac, MD, PhD, Department of Pharmacology, Victor Babes University of Medicine and Pharmacy Timisoara, 2 E. Murgu Square, Timisoara, Tel. +40-746-976871
Email: beabarac@yahoo.com
REZUMAT
Obiectiv: Scopul actualului studiu a fost de a analiza actiunea farmacodinamica a statinelor administrate in regim intensiv comparative cu regimul in doze moderate la pacientii coronarieni cu profil lipidic plasmatic alterat. S-au urmarit: regresia grosimii intime-medii arteriale la nivelul arterelor carotide comune (IMT carotidian), reducerea markerului biologic inflamator proteina C reactiva (PCR) si modificarea profilului lipidic plasmatic. Material si metode: Lotul de studiu a cuprins un numar de 57 pacienti cu boala coronariana, care au fost urmariti pe o perioada de 6 luni. Protocolul general de studiu a presupus recoltarea de probe biologice si studiu prin ecocardiografie vasculara. Rezultate: S-a demonstrat astfel ca terapia cu statine in doze mari, a redus IMT carotidian cu valori intre 9,57% si 7,78% in timp ce markerul inflamator PCR a fost redus in medie cu 20,5-25,6 %. Comparativ la doze moderate IMT s-a redus cu 3,95-5,84% iar PCR serica a avut la finalul studiului cu valori 5,2-6,9% mai mici. in grupul tratat cu statine in doza mare colesterolul total seric s-a redus cu 31,7-33,8%, LDL colesterolul seric s-a redus cu 38,6-41,8%, in timp ce HDL colesterolul seric a crescut cu 3,3-3,7%. Comparativ, in grupul cu regim moderat s-au obtinut valori cu 17,2-17,5% mai mici pentru colesterolul seric total, cu 22,9-23% mai mici pentru LDL colesterol si cu 3,01-2,09% mai mari pentru HDL colesterol. Concluzii: Eficienta terapeutica a statinelor este proportionala cu doza in ceea ce priveste actiunea farmacodinamica de modulare a procesului aterosclerotic fapt demonstrat prin reducerea PCR serice si a IMT carotidian.

ABSTRACT
Objective: The purpose of the present study was to compare the pharmacodynamic action of high and moderate doses of statin therapy, administered to patients with coronary artery disease and altered plasma lipid profile. The following aspects will be considered: the regression of arterial intima-media thickness (IMT), the reduction of the biological inflammatory marker C-reactive protein (CRP) and the modulation of the plasma lipid profile. Material and methods: The study was conducted on 57 patients with coronary heart disease. The patients were followed for six months. The study protocol required both biological sample collection and vascular ultrasound to be performed initially and after 6 months of therapy. Results: It has been demonstrated that in subgroup with high doses of statin therapy, carotid IMT was reduced with 7.78-9.57%, and the CRP was reduced with 20.5-25.6%, while in subgroup treated with moderate doses of statins, IMT decreased with 3.95-5.84%, and the serum CRP value with 5.2-6.9%. High doses statin therapy reduced total serum cholesterol with 31.7- 33.8%, serum LDL cholesterol with 38.6-41.8%, while serum HDL cholesterol increased with 3.3-3.7%. Moderate dose statin therapy reduced the values of the total serum cholesterol with 17.2 -17.5%; serum LDL cholesterol decreased with 22.9-23%, and HDL cholesterol increased with 2.09-3.01 %. Conclusions: The efficiency of statins therapy on the plasma lipid profile and the subsequent actions of reducing the atherosclerotic process, revealed by CRP and IMT reduction is proportional with the dose.
INTRODUCTION

The introduction of statins (HMG-CoA reductase inhibitors) in the therapeutic management of patients with coronary artery disease (CAD) and dyslipidemia is a key step in the pharmacological therapy of this century.1-12 It has been demonstrated that the progress of the atherosclerotic disease is an active pathological process involving a series of cascade reactions that include lipid accumulation and the infiltration of macrophages and fibrocellular components in the intimal media of the vascular arterial wall.12-20 The pharmacodynamic action of the HMG-CoA reductase inhibitors at the level of the atherosclerotic process is reflected biologically in the reduction of inflammatory markers, particularly in the decrease of C-reactive protein (CRP) after statin therapy. Recently, the benefits of high-dose statin therapy against the evolution of atherosclerotic disease in coronary arteries have been explained through the reduction of serum C-reactive protein, rather than through the decreased serum LDL-cholesterol values.21-25

The use of noninvasive imaging methods has made possible to monitor the effects of pharmacological therapy on the changes in atherosclerotic plaques in larger arteries, especially in the carotid arteries by measuring intima media thickness (IMT).6-12

While the invasive intravascular ultrasound methods allow the accurate quantification of plaque volume, the non-invasive vascular ultrasound examination of carotid arteries for the IMT index has proved to be a very good predictive method reflecting the severity of the coronary disease.7-15 In addition, IMT measurement is a good indicator of the incidence of cardiovascular events. The regression of the carotid IMT has been demonstrated in all patients with familial hypercholesterolemia, while in other clinical studies IMT was a comparative index between different pharmacological agents.17-23 Furthermore, in recent trials, atorvastatin has proved more effective in reducing plaque volume in coronary arteries, compared to fibrates, colestiramine and other statins.7-15

As far as CAD patients are concerned, the role of statin therapy in reducing the intima media thickness has not been entirely demonstrated yet.25-38

OBJECTIVES

The principal aim of the present study was to compare the pharmacodynamic action of high dose dose statin therapy (atorvastatin 80 mg/day, rosuvastatin 40 mg/day) with the moderate doses (simvastatin 40 mg/day, atorvastatin 20 mg/day, rosuvastatin® 20 mg/day, lovastatin 40 mg/day) administered to coronary patients with altered plasma lipid profile. The following aspects were considered:
a) the regression of carotid IMT in CAD patients with mixed dyslipidemia of pleiotropic etiology;
b) the slowing down of the atherosclerotic process through the reduction of the biological inflammatory marker C-reactive protein (CRP);
c) the improvement of the plasma lipid profile, in order to achieve the target recommended by specialty guidelines regarding plasma LDL cholesterol, as this is the main risk factor in CAD and stroke.

The tolerability and safety profile relative to drug dosage and the analysis of potential acute events and general and cardiovascular mortality have been chosen as secondary objectives of this study.

MATERIAL AND METHOD

A randomized, open-label, clinical, prospective, comparative study was conducted on 57 patients with CAD hospitalized in the Cardiology Clinic of the Institute of the Cardiovascular Disease from Timisoara from June to Octomber 2008. The patients were followed for six months. All patients included in the study received instruction and counselling to promote compliance with the NCEP (National Cholesterol Education Program - Adult Treatment Panel II) for the use of pharmacological hypolipemic drug therapy. The study was performed in accordance with the ethical principles set forth in the Declaration of Helsinki and was approved by the local ethics committees.
The patients were selected based on inclusion and exclusion criteria (detailed below), a research protocol and a monitoring form. Two comparative evaluations were performed, one initially and one after 6 months of pharmacological therapy.

Patient inclusion criteria were the following: clinically proved coronary artery disease; hyperlipidemia – total cholesterol levels over > 200 mg/dl, and/or HDL cholesterol <40 mg/dl in males and < 50 mg/dl in females, and/or LDL cholesterol > 100 mg/dl; the patients good cognitive functions, able to understand and comply with the study protocol.

Patient exclusion criteria were: severe systemic disease; associated infectious disease; chronic inflammatory disease; severe hepatic and renal affections; neoplasia; treatment with estrogen per os, anabolic steroids, progestatives, carbamazepine; significant carotid atherosclerosis (> 70% luminal stenosis or dissection with indication for percutaneus angioplasty or thrombond arterectomy); short thick neck that did not allow carotid ultrasound evaluation; statin intolerance, patients previously allergic to statins or statin idiosyncrasy; previous severe allergic reactions of any type, especially the Stevens-Johnson syndrome, toxic epidermal necrosis; previous alcoholism or iatrogenic disease; lack of acceptance of treatment or of the study protocol; pregnancy and breast-feeding.

The general study protocol required both biological sample collection and vascular ultrasound to be performed initially and after 6 months of therapy: carotid Doppler ultrasound was performed for the evaluation of carotid IMT and the collection of blood samples for the evaluation of the following biological parameters of the plasma lipid profile: total cholesterol, HDL cholesterol, LDL cholesterol, serum triglycerides. Therapeutic efficacy was also evaluated biologically, by measuring the serum acute phase reactant, CRP, which was collected both at the beginning and at the end of the study.
The study included a final clinical re-evaluation of the patients and the collection of data concerning the safety and tolerability profile. The patients were instructed to report any major/minor adverse reactions or any hospitalization subsequent to cardiovascular disease occurring during the study.

Group randomization
The initial group (57 patients) was randomized in two subgroups based on a unique criterion, the initial total serum cholesterol. Subgroup A included 41 (71.9%) patients with total serum cholesterol under 300 mg/dl, 14 (34.1%) women and 27 (65.9%) men.Subgroup B included 16 (28.1%) patients with total serum cholesterol over 300 mg/dl, 4 (25%) women and 12 (75%) men.

Table 1. Percentage distribution after the type of statin therapy in subgroups A and B randomized according to the plasma lipid profile, in par [...]
Pharmacological treatment
After the randomization according to their total serum cholesterol level, statin therapy started as follows: subgroup A included patients with total serum cholesterol under 300 mg/dl receiving moderate statin therapy: 20-40 mg/day of simvastatin®, 20 mg/day rosuvastatin®, 20 mg/day atorvastatin® or lovastatin®; subgroup B included patients with total serum cholesterol over 300 mg/dl receiving intensive statin therapy: high doses of two types of statins, 80 mg/day atorvastatin® or 40 mg/day rosuvastatin®. The atorvastatin® therapy started with 20 mg/day and was increased gradually to a maximum dose of 80 mg/day in three weeks.
The preparations were administered as a single daily dose in the evening. (Table 1)

Paraclinical monitoring and laboratory biological samples
Carotid Doppler ultrasound for the evaluation of carotid intima media thickness
All studied patients (n=57) were examined with a 7.5 MHz linear transducer ultrasound. PHILIPS SONOS 5500 and 7500 ultrasound systems were used. Longitudinal and transverse views of the common carotid artery, the bifurcation and the internal and external carotid arteries were obtained. IMT was measured at the level of the common carotid artery, one centimetre before the carotid bifurcation; the maximum thickness was recorded and the evaluation was bilateral. The data were video recorded and processed afterwards, both at the beginning of the study and after 6 months of therapy.

Evaluation of serum C-reactive protein (CRP) level
Biological samples were taken from all 57 patients of the initial group for CRP determination at the beginning of the study and after 6 months of statin treatment. CRP was determined by the immunoturbidimetry methods with COBAS INTEGRA® 400 (Roche) analyzer, with detection limits from 0 to 6 mg/dl.

Evaluation of plasma lipid profile
Blood samples were taken from the patients at the next of the study and after 6 months of treatment for the evaluation of the plasma lipid profile.
The total cholesterol in serum HD and higlycerides assesed by an enzyme mediated a spectrometer.

Statistical analysis

The statistical analysis was performed on a computer file created with Microsoft Excel and managed in databases.

The two subgroups, A and B were analyzed comparatively, the initial results of the blood tests and of the ultrasound evaluation were compared with the final ones, obtained after six months of treatment with statins.
The statistical data processing was performed using EPI 3.2.2, SPSS 10, OpenEpi 2.3. The parametric variables before and after therapy in each subgroups were compared by paired sample t test. The comparison of parametric variables between the two subgroups was performed by unpaired t test. All data were expressed as mean ± standard deviation (SD) and also percentage. A p value < 0.05 was considered statistically significant.

RESULTS

Table 2. Randomization of patients according to the type of therapy they started at their inclusion in the study.
The clinical, paraclinical and laboratory characteristics of the patients randomised according to the type of therapy are shown in Table 2.

Evaluation of the therapeutic efficacy on maximum carotid IMT
The results of this study revealed that atorvastatin doses of 80 mg/day and rosuvastatin doses of 40 mg/day reduce IMT in females with 0.14 mm (9.57%)-0.12 mm (8.29%)(p = 0.001) and in male patients, with 0.146 mm (9.73% )-0.11 mm (7.78%)(p < 0.001).
In the female patients of subgroup with moderate therapy, maximum IMT was reduced with 0.042 mm (3.95%)-0.07 mm (5.04%) (p < 0.001). In male patients, the IMT reduction was 0.081 mm (5.84%)-0.06 mm (4.58%) (p < 0.001). (Fig. 1)

Evaluation of the therapeutic efficacy on the serum C-reactive protein level
In the female subjects of A subgroup, the CRP was reduced with 0.10 mg/dL (5.2%) (p < 0.001). In the male subjects, the marker decreased with 0.13 mg/dL (6.9%) (p < 0.001) after 6 months of treatment.
Comparatively, in the intensive therapy subgroup B serum, CRP had the following evolution: at the end of the study, CRP decreased with 0.635 mg/dL (20.5%) (p > 0.05) in female patients and with about 0.81 mg/dL (25.6%) (p < 0.001) in the male patients. (Fig. 2)

Figure 1. Average of numerical and percentage differences between maximum IMT values at the beginning of the study and after 6 months of therap [...]
Figure 2. Average of numerical and percentage differences between C-reactive protein values at the beginning of the study and after 6 months of [...]

Evaluation of the therapeutic efficacy on the plasma lipid profile
The plasma lipid profile suffered positive changes in both subgroups; however, the changes in the patients under intensive therapy proved to be superior. Serum total cholesterol decreased between 17.2% and 17.5% in subgroup A, compared to subgroup B, where the decrease was between 33.8% and 31.7%. In subgroup A, serum LDL cholesterol decreased between 22.9 and 23% compared to subgroup B, in which the decrease were significantly higher: between 38.6% and 41.8%. In subgroup A, serum HDL cholesterol increased with 3.3-3.7%, while in subgroup B with only 3.01-2.09%. Serum triglycerides decreased between 6.8 and 6.9% in subgroup A, compared to 17.4-18.3% in subgroup B. (Fig. 3)

Final patient distribution within the study subgroups
Of the initial 57 patients, only 52 (91.2%) reached the end the study. During the 6 months of therapy, 2 patients died – of non-cardiovascular reasons (3.5%) and 3 of them (5.3%) did not come for parameter re-evaluation.

Analysis of the safety and tolerability profile
In the 6 months of therapy, 8 patients (14.0%) were rehospitalized: 3 patients (7.3%) from subgroup A – 2 for unstable angina and 1 for ischemic stroke; 5 patients (31.3%) from subgroup B–3 patients for unstable angina and 2 for coronary angioplasty.
As far as the incidence of adverse reactions during the study are concerned, they were reported by the patients and recorded in the specific monitoring forms. The most common aspects were taken into consideration: muscular, digestive and neuropsychical disorders. No serious adverse event occurred (such as hepatitis or myositis) and all the reactions resolved following discontinuation of the drug therapy. The frequency of adverse events was higher in subgroup B. Myalgia (78.6%), muscle spasms (42.9%), muscle weakness (71.4%), and insomnia (64.3%) were the most commonly events in subgroup B, but they were less frequent in subgroup A. All digestive reactions were more frequent in subgroup B and less frequent in subgroup A. (Fig. 4)

Figure 3. Average of numerical and percentage differences between the values of the plasma lipid profile parameters at the beginning of the stu [...]
Figure 4. Comparative presentation of adverse effects in subgroups A and B.

DISCUSSION

In this study, the demographic data show the high risk of vascular and coronary acute events in cardiovascular patients suffering from familial hypercholesterolemia. The study group consisted of patients with CAD and with numerous associated risk factors for vascular events, while the pharmacological intervention with lipid-lowering therapy was prescribed for their secondary prophylaxis. The marked atherogenic plasmatic profile of these patients highly predisposes to cerebrovascular accidents, especially due to the high level of LDL-cholesterol-the mean value in females: 154.5 mg/dL (15.2 SD), respectively 155.1 mg/dL (19.0 SD) in males. The mean level of HDL cholesterol was 41.5 mg/dl (0.8 SD) in females and 40.9 mg/dl (0.7 SD) in males. Also, one may note the high level of seric CRP in all patients with high common carotid artery IMT among the studied population.

The results of this study revealed a superior high efficiency from pharmacodynamic point of view of the administered treatment/dose in intensive regimen comparatively with the moderate dose, concerning all the monitored parameters, but at the price of a lower tolerability, and this aspect has been reflected in the incidence of side effects in both subgroups.

Modulation of atherosclerotic plaque burden is a new treatment target in patients with CAD.6-12
It has been shown that atherosclerosis is not a focal disease but a "systemic" condition that also affects other major arteries of human body and the progression of atherosclerotic plaque is an active disease process that involves a cascade of reaction in the arterial wall.12-15 While accurate quantification of atherosclerotic plaque volume in the coronary arteries is possible by invasive intravascular ultrasound, examination of carotid arteries for IMT is proved to be a reliable marker to reveal the severity of atherosclerosis and to predict the presence of CAD.6-15 IMT is also shown to be a strong indicator for adverse cardiovascular events.8, 15-17, 18-21 In one double-blind, randomized, controlled study, it was observed that high dose atorvastatin not only prevented the progression of atherosclerotic plaque formation in the carotid arteries but also actually regressed the IMT by up to 10% after 26 weeks. This was in contrast to the low dose regimen that only prevented the progression of carotid disease.21

In ASAP study, 325 subjects with familial hypercholesterolemia who had very high cholesterol levels were randomised to atorvastatin 80 mg daily or simvastatin 40 mg daily for 24 months, and regression of carotid IMT was observed only in the atorvastatin group.16
The benefit of intensive atorvastatin therapy in our study of maximum IMT levels in the study enrollment and after 6 months of hypolipemiant therapy reveals the clear superiority of the statin therapy in intensive regimen comparatively with the moderate therapy.
Recently, the benefit of high dose atorvastatin therapy in preventing the progression of atherosclerotic plaque in coronary arteries was explained by the favorable reduction of CRP rather than LDL cholesterol levels.3,4 In PROVE-IT study, those patients who had improvement of both LDL cholesterol and CRP levels after statin therapy had the most favorable clinical outcome.5 In other studies it was also revealed that aggressive atorvastatin therapy is able to modify atherosclerotic plaque by reducing the inflammatory activity that may be associated with the reduction of CRP levels. A recent study reported that the CRP level was decreased by 65% in the high dose group, but showed a trend to increase in the low dose group.21
Large randomized clinical trials confirmed the superiority of high doses of atorvastatin (80 mg/day) in reducing stroke in comparison with a moderate regime with atorvastatin doses of 10-20 mg/day or pravastatin, 40 mg/day in coronary patients.1-5 This aggressive therapy determines the reduction of serum LDL cholesterol under 80 mg/dL (<2.07 mmol/L), a level which is far lower than the one recommended by the current guidelines (LDL <100mg/dL).27

The results of the present study concerning the modification of the plasma lipid profile show that high doses of atorvastatin or rosuvastatin lowered the plasmatic LDL-cholesterol level under 100 mg/dl in all patients from subgroup B, a level proposed by NCEP ATP III as the target for secondary prophylaxis of cardiovascular diseases in patients with familial hypercholesterolemia, especially in cases of acute myocardial infarction, stroke or in patients with diabetes mellitus. Comparatively, this target was not reached in patients treated with moderate doses of statins. The plasma lipid profile modified in a positive way in both cases, with proven superiority in patients from the group that underwent intensive therapy.

Our study, adjacently to other main studies1-4 on the classical therapeutic action of statins on the lipid metabolism and modulation of atherosclerosis, confirms that the high doses of statins exercise significantly higher anti-inflammatory effects against C-reactive protein, comparatively with the moderate dosage regimens, with complex and favorable therapeutic implications in cardiovascular patients.

CONCLUSIONS

The statin therapy remains one of the most efficient methods in reducing the risk of cardiovascular disease in the patient with the presence of cardiovascular risk and the spoiling of the cardiovascular patient with the presence of cardiovascular risk factors.

The therapeutic efficacy of statins is dose-dependant, regarding both the main pharmacodynamic effect on the plasma lipid profile and the secondary actions in reducing the atherosclerotic process by modulation of the inflammatory biological marker – seric CRP - or of the paraclinic marker – the carotidian IMT. All these three parameters can be significantly modified mostly by intensive dosage regimens comparatively with the moderate dosage regimens in the patients with CAD and mixed dyslipidemia of pleiotropic etiology.
At high doses of statin therapy, the extensive pharmacodynamic action is associated with an alteration of the tolerability profile in comparison with the moderate dosage regimen, and therefore it is required to rigorously follow-up the patient and the laboratory parameters , afferent to the hepatic or renal deteriorations and any other side-effect occurring during the therapy.

The physician must adjust the therapeutic doses for each patient individually, taking into account the level of plasma lipid fractions and the possible presence of other chronic diseases, especially hepatic or renal disease. The clinical study on the efficacy of statin treatment associated with the control of risk factors of atherosclerosis in CAD patients with carotid atheromatosis reveals the efficacy of statins on the reduction of the atherosclerotic risk and subsequent complications, besides the pleiotropic effects reflected in the modulation of the endothelial function, coagulation and plaque stabilization.
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