The Effect of Short-term Lipid Lowering With Atorvastatin on Carotid Artery Intima Media Thickness in Patients With Peri

[알프레드]

The Effect of Short-term Lipid Lowering With Atorvastatin on Carotid Artery Intima Media Thickness in Patients With Peripheral Vascular Disease: A Pilot Study
M. Davis [1] , A. S. Atwal [1] , D. R. Nair [2] , I. A. Jagroop [2] , A. M. Seifalian [1] , D. P. Mikhailidis [2] and G. Hamilton [1]

[Current Medical Research and Opinion 16(3):198-204, 2000. © 2000 LibraPharm Limited]


Summary
The effect of rapid lipid lowering (with 20 mg/day of atorvastatin) on common carotid artery intima media thickness (IMT) in patients (n = 12) with peripheral vascular disease was studied. Fasting blood samples and IMT measurements were carried out at baseline and repeated after 8 weeks treatment.. Total cholesterol decreased significantly by 27% (p < 0.0005) and low-density lipoprotein (LDL) cholesterol by 41% (p < 0.001). The rapid reduction in lipid profiles was mirrored by a significant (p < 0.001) reduction of 15.3% in common carotid artery IMT.

Introduction
In a systematic review of the literature, Herbert et al. [1] demonstrated large reductions in cholesterol and clear evidence of benefit on stroke morbidity and total mortality following treatment with statins. There was a significant reduction in both the risk of stroke [29% (95% confidence interval (CI), 14 41%)] and overall mortality [22% (95% CI, 12 31%)]. Statins may decrease the risk of stroke by preventing or reversing atherosclerosis in the extracranial arteries [2].
Carotid artery intima media thickness (IMT) is a strong predictor of cardiovascular and cerebrovascular events [3,4]. For example, in the Atherosclerosis Risk in Communities (ARIC) Study [3] , 15 792 men and women aged 45 64 years were followed for 4 7 years for incidences of cardiac disease. There was a positive association between IMT and coronary disease in younger subjects [5]. In another study, IMT was directly associated with an increased risk of myocardial infarction and stroke in older patients without a history of cardiovascular disease [4].

Several recent trials have shown an association between raised total cholesterol and carotid atherosclerosis [6,7]. The IMT can be reduced by cholesterol-lowering treatment. For example, Furberg et al. [8] demonstrated that, over a three-year period, lovastatin caused a significant (p = 0.001) regression in carotid IMT as well as a reduction in cardiovascular events (p = 0.04) and mortality (p = 0.02). Similarly, a sub-study of the LIPID trial [9] showed that pravastatin significantly reduced the IMT of the common carotid artery (p < 0.0001) after treatment for four years.

We investigated the association between rapid lipid-lowering therapy and carotid artery IMT in patients with established peripheral vascular disease (PVD) and no known carotid artery pathology. Patients with PVD have been shown to have an increased carotid artery IMT compared with controls [10]. Our hypothesis was that aggressive, lipid-lowering therapy may not only reduce total cholesterol levels, but also improve carotid artery IMT in a short time period (eight weeks).


Patients and Methods
Patients (n = 12) with primary hypercholesterolaemia and PVD were selected from the outpatient clinics. The presence of PVD was assessed by the following criteria:

Ankle brachial pressure index (ABPI) < 0.8 at rest, with a fall on exercise.

History of PVD for at least six months, with no radiological or surgical intervention.

A maximum walking distance (MWD) of 50 450 m.

Reproducible exercise test with an MWD within 30% on two occasions.

Exclusion criteria were:

Women of child-bearing potential.

Calf pain at rest.

Previous carotid endarterectomy or carotid artery stenosis (> 69%).

Other significant medical conditions affecting exercise potential, e.g. asthma, rheumatoid arthritis/ osteoarthritis, recent myocardial infarction, heart failure or angina.

Central nervous system diseases resulting in decreased mobility or caused by carotid artery pathology.

Diabetes mellitus types I and II..

All venous samples were collected following a 14 h fast. Patients were recruited if they had primary hyperlipidaemia and were not receiving any lipid-lowering medication.
Metabolic and haemodynamic parameters were measured at baseline and at eight weeks post-treatment with atorvastatin 20 mg/day.

On both visits the following measurements were made:


Haematological and biochemical (fasting) profiles (see Results for details).

Blood pressure, heart rate, height and weight.

ABPI performed pre-exercise and post-exercise. The exercise test was performed using a treadmill at 3 km/ h with a 10% gradient.

Common carotid artery IMT measurement (see below).

All patients were given dietary advice, and following baseline fasted blood sampling and IMT measurements, all were commenced on atorvastatin 20 mg orally, at night.
Fasting blood profiles were analysed by the hospital laboratories that are clinical pathology accredited (CPA).


Fibrinogen Assay
Plasma fibrinogen was measured in citrated samples using the Clauss method as previously described [11].

Homocysteine Assay
Plasma homocysteine concentration was measured by a method based on HPLC (Drew Scientific, Park Road, Barrow in Furness, Cumbria) in fasting samples.

Assessment of Common Carotid Artery Intima Media Thickness (IMT)
A vessel-wall tracking system was used, consisting of a conventional ultrasound imaging system with a software programme (Scanner 350, Pie Medical Systems, Maastricht, The Netherlands). A two-dimensional B-mode image of the right common carotid artery was gained 2 cm proximal to the carotid bifurcation in a region of the vessel free from plaque. IMT measurements were taken three times, gaining four values on each occasion, from which a mean value was calculated.

Data Collection and Statistical Analysis
All analyses were performed using the SPSS version 9 for Windows statistical software programme. Values are expressed as median and range; p < 0.05 was considered statistically significant, using non-parametric Wilcoxon signed rank sum tests (two-tailed).

Results
Baseline Characteristics (Table 1)
There was no significant difference in these characteristics between baseline and visit two at eight weeks.

ABPI, Pain-free Walking Distance and Maximum Walking Distance
There was no significant difference in these characteristics between baseline and visit two at eight weeks (Table 2).

Biochemical and Haematological Profiles (Tables 3-6)
In both pre-atorvastatin therapy and post-atorvastatin therapy, the full blood count remained within the reference range (results not shown).
No significant differences either before or after atorvastatin therapy were noted for renal, liver and thyroid function tests. The liver function tests remained within the reference range (results not shown).

Plasma fibrinogen and creatinine concentrations, as well as creatine kinase (CK) activity, are shown in Table 3. There was no significant change in these variables during the treatment period.

No significant difference was found in fasting plasma homocysteine levels and the related vitamins (serum B12, folate or red cell folate) after eight weeks of atorvastatin (Table 4). At baseline 10 out of 12 (83%) patients had serum homocysteine levels of 11 [infinity][infinity][infinity][infinity][infinity][infinity] or higher a value which may warrant treatment [12].

After eight weeks treatment there was a significant reduction in fasting total cholesterol ( 27%), low-density lipoprotein (LDL) cholesterol ( 41%) and triglycerides ( 25%) (Table 5). At baseline, all the patients (n = 12) had an LDL cholesterol level of > 3 mmol/l, whereas after eight weeks of atorvastatin treatment 11 out of 12 patients (92%) had achieved an LDL cholesterol level of [infinity] 3.0 mmol/l; the level recommended by the Joint British Guidelines [13]. The high-density lipoprotein (HDL) cholesterol levels did not change significantly. However, the LDL:HDL ratio, a well-established index of cardiovascular risk [13] , was significantly (p = 0.007) improved (Table 6) both pretreatment and post-treatment.


Assessment of Common Carotid Artery Intima Media Thickness (IMT)
The median IMT was significantly (p < 0.001) reduced (by 15.3%, from 0.98 mm (0.68 - 1.18 mm) to 0.83 mm (0.65 - 0.99 mm)) after eight weeks treatment with atorvastatin.

Discussion
As expected, atorvastatin significantly lowered LDL cholesterol and triglyceride levels. We also found that after only eight weeks of treatment with atorvastatin, the common carotid IMT was significantly (p < 0.001) reduced. In earlier trials, Furberg et al. [8] and MacMahon et al. [9] demonstrated a significant statin-related regression in carotid IMT; however, treatment was over a period of years. Other studies have also shown a benefit in terms of retardation of extracranial atherosclerosis following the long-term use of statins (PLAC-II [5] , CAIUS [14] , KAPS [15] ). We suggest that atorvastatin produces a rapid decrease in IMT and that this effect is probably sustained for several years.
In the LIPID trial, which recruited patients post-myocardial infarction, the risk of stroke as well as cardiovascular morbidity and mortality were significantly reduced [9]. In a sub-study from this trial, IMT was significantly reduced in the patients treated with pravastatin for four years [9]. In contrast, those on placebo had the expected increase in IMT [9]. It is, therefore, possible that a reduction in IMT is a marker of efficacy (i.e. morbidity/mortality). In the Scandinavian Simvastatin Survival Study (4S) [16] , cholesterol lowering was associated with a significant (p = 0.009) reduction (48%; 95% CI: 15 68%) in new or worsening carotid bruits over a five-year period. These findings were accompanied by a significant (p = 0.024) reduction (30%; 95% CI: 4 48%) in the combined end point of transient ischaemic attack (TIA) and stroke. These findings suggest that treatment with simvastatin improves carotid artery rheology and that this translates into a clinical benefit at least in patients with clinically evident coronary artery disease.

The molecular mechanism by which a rapid decline in IMT is brought about is suggested by work performed by Igarashi et al. [17]. They showed in a rabbit model that cerivastatin prevents macrophage accumulation in the intima. This effect contributes to the inhibition of intimal thickening.

The rapid changes in IMT documented in the present study parallel those seen at a functional level. For example, O Driscoll et al. [18] demonstrated that endothelial function (as represented by forearm blood flow) of patients with moderately elevated serum cholesterol improved rapidly within one month of commencement of simvastatin therapy. A similar rapid improvement in endothelial function was reported following six weeks of therapy with pravastatin [19].

There was no trend towards an increase in fibrinogen levels in the present study. Fibrinogen is an independent predictor of myocardial infarction and cerebrovascular events [20,21]. The effect of different statins on fibrinogen level is variable [22].

Serum homocysteine levels were high, as expected in PVD [12]. Unlike the reports of a rise in homocysteine levels after fibrate therapy [23,24] , we did not observe such a change with atorvastatin.

The incidence of vascular events and death among patients with PVD is higher than in the normal population [25]. At least 70% of patients with intermittent claudication have ischaemic heart disease and their 10-year mortality from vascular disease, largely due to myocardial infarction and stroke, is approximately 50%, or 3.8 times greater than for patients without PVD [26]. The outlook for patients with critical limb ischaemia is even worse; one in five will die from cardiovascular disease within a year of diagnosis [27]. Therefore aggressive risk factor modification is imperative in patients with PVD.

At present, risk factor assessment and treatment is based on target values. In addition, it may be appropriate to monitor an anatomical end point (e.g. IMT) so as to establish that preventive treatment is effective in each case. This proposal requires further validation and has obvious cost implications. Such an index must be reproducible and significantly altered soon after initiation of treatment.

In conclusion, atorvastatin significantly (p < 0.001) and rapidly (eight weeks) reduced the carotid IMT. Larger trials are required to confirm‎ the findings of our pilot study. Monitoring the IMT may offer a novel method to ensure effective treatment in each patient.


Table 1. Patient characteristics at baseline visit. Values are expressed as median (range) where appropriate
Characteristic
Value

No. of patients
12

Age (years)
71.5 (46 78)

Men (%)
9 (75%)

Body mass index
27 (21.8 33.3)

Current smokers (%)
6 (50%)

Systolic blood pressure (mmHg)
155 (120 180)

Diastolic blood pressure (mmHg)
80 (70 100)

Medication:

No. receiving antihypertensives
2

No. receiving aspirin
11




Table 2. The results of the treadmill exercise tests performed at baseline and at eight weeks. ABPI = ankle brachial pressure index; NS = not significant

ABPI pre-
exercise
ABPI post-
exercise
Pain-free walking
distance (m)
Maximum walk-
ing distance (m)

Pre-atorvastatin
0.63 (0.42 0.88)
0.30 (0.00 0.46)
150 (30 300)
215 (80 430)

Post-atorvastatin
0.68 (0.45 0.87)
0.35 (0.00 0.50)
150 (30 320)
230 (80 450)

Significance
NS
NS
NS
NS




Table 3. Serum creatine kinase (CK) activity, plasma fibrinogen and serum creatinine levels in patients before and after atorvastatin therapy

CK (U/l)
Fibrinogen (g/l)
Creatinine (µmol/l)

Pre-atorvastatin
125 (32 125)
355 (208 478)
85 (75 137)

Post-atorvastatin
124 (30 86)
354 (223 439)
82 (74 144)

Significance
NS
NS
NS




Table 4. Fasting levels of homocysteine, vitamin B12, folate and red cell folate before and after atorvastatin therapy

Vitamin B12
(ng/l)
Folate (µg/l)
Red cell folate
(µg/l)
Homocysteine
(µmol/l)

Pre-atorvastatin
435 (289 965)
4.5 (2.5 8.7)
222 (130 658)
13.1 (6.4 21.1)

Post-atorvastatin
438 (281 558)
6.5 (2.5 9.7)
233 (172 778)
15.4 (3.6 23.6)

Significance
NS
NS
NS
NS




Table 5. Fasting lipid profiles before and after eight weeks treatment with atorvastatin (20 mg/day)
Fasting lipid
profile
Total cholesterol
(mmol/l)
HDL cholesterol
(mmol/l)
LDL cholesterol
(mmol/l)
Triglycerides
(mmol/l)

Pre-atorvastatin
6.2 (5.5 7.8)
1.7 (0.8 2.3)
3.9 (3.0 5.3)
1.9 (0.8 5.7)

Post-atorvastatin
4.5 (3.4 5.8)
1.6 (0.8 2.2)
2.3 (1.8 3.5)
1.4 (0.6 3.2)

Significance
p < 0.0005
NS
p < 0.001
p < 0.04




Table 6. LDL:HDL ratio pre-treatment and post-treatment with atorvastatin (20 mg/day)

LDL:HDL ratio

Pre-atorvastatin
2.55 (1.43 4.48)

Post-atorvastatin
1.55 (0.95 3.86)

Significance
0.007




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