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The Early Effect of Lipid-lowering Treatment on Carotid and Femoral Intima Media Thickness (IMT)
Eur J Vasc Endovasc Surg 23, 358–364 (2002) doi:10.1053/ejvs.2002.1611, available online at http://www.idealibrary.com on
The Early Effect of Lipid-lowering Treatment on Carotid and Femoral Intima Media Thickness (IMT)† F. Youssef1, A. M. Seifalian1, I. A. Jagroop2, F. Myint1, D. Baker1, D. P. Mikhailidis2 and G. Hamilton1 1
University Department of Surgery and 2Department of Clinical Biochemistry, Royal Free Hospital NHS Trust and Royal Free and University College Medical School, University College London, London, U.K. Objectives: an increased intima media thickness (IMT) is an early indicator of the atherosclerotic process. We investigated the early effect of atorvastatin on the common carotid artery (CCA) and common femoral artery (CFA) IMT. Methods: the IMT was measured in the CCA and the CFA of hyperlipidaemic patients referred with peripheral vascular disease. The measurements were performed using an automated radio frequency IMT technique pre-treatment and at 4 and 8 weeks post-treatment with 20 mg/day atorvastatin. Results: patients (14 men; 11 women), median age 69 years (range: 48–81) had a CCA-IMT mean (SD) of 0.79 (0.21) mm pre-treatment, 0.75 (0.22) mm after 4 weeks, and 0.64 (0.15) mm after 8 weeks. The ANOVA test was significant (p= 0.024) for the CCA-IMT trend. The corresponding CFA-IMT readings were 0.83 (0.13) mm, 0.80 (0.09) mm and 0.69 (0.14) mm (p=0.0003). After 8 weeks of treatment there was a significant reduction in total cholesterol 6.0 (0.3) to 4.3 (0.8) mmol/l, p=0.0004 and low-density lipoprotein cholesterol 3.7 (0.2) to 2.2 (0.5), p=0.0001. There was a significant decrease in median serum creatinine levels after 8 weeks treatment: 87 mol/l (range 67–114) to 84 mol/l (range: 64–112), p=0.007. Conclusions: cholesterol-lowering with atorvastatin 20 mg/day leads to a decrease in CCA-IMT and CFA-IMT. This difference achieved significance after 8 weeks of treatment, but a trend was visible at 4 weeks. These rapid changes in IMT may be attributable to an anti-inflammatory effect. IMT measurement may be a useful tool to rapidly assess the effect of drug treatment on the atherosclerotic process. Key Words: Atorvastatin; Intima media thickness; Femoral; Carotid; Creatinine; Peripheral vascular disease; Urate.
Introduction The common carotid artery intima media thickness (IMT) (CCA-IMT) can be measured accurately noninvasively.1–5 Furthermore, an increased CCA-IMT is associated with major cardiovascular risk factors and is a powerful predictor of cardiovascular events, particularly those associated with ischaemic heart disease (IHD).6–9 In 133 patients the severity of coronary disease, as shown by coronary angiography, was significantly correlated with the CCA-IMT when measured by ultrasonography.10 Increased CCA-IMT is strongly associated with a risk of stroke11 and small changes in the CCA-IMT were also associated with clinically significant atherosclerosis in the peripheral ∗ Please address all correspondence to: G. Hamilton, Consultant Vascular Surgeon, Vascular Unit, University Department of Surgery, Royal Free Hospital NHS Trust, Pond Street, London NW3 2QG, U.K. † Presented at the XV Annual Meeting of the European Society for Vascular Surgery (ESVS), Switzerland (September 2001) and awarded the prize of the best paper presentation in the junior vascular surgeon session.
arteries.12 There are only a few studies involving the common femoral artery IMT (CFA-IMT). They showed that the combined assessment of the carotid and femoral arterial walls provides a more accurate estimate of the atherosclerotic burden in patients with familial hyperlipidaemia.13 The femoral and carotid IMT was also increased in smokers without other vascular risk factors.14,15 B-mode (two-dimensional) duplex ultrasound is also increasingly used for non-invasive visualisation and monitoring of atherosclerotic changes in the vasculature. Its use in measuring the CCA-IMT is now established as a method.16–19 It can be concluded from these studies that the IMT may represent the sum of the cardiovascular risk in an individual. Therefore, the IMT is expected to be increased in those with established vascular disease. Cholesterol-lowering treatment effectively prevents IHD-related events and strokes20,21 and also significantly reduces overall mortality in patients with established IHD.22 In turn, hyperlipidaemia predisposes to an increased CCA-IMT23 and cholesterollowering treatment causes CCA-IMT regression.24,25 Therefore, we monitored the CCA-IMT and CFA-IMT
1078–5884/02/040358+07 $35.00/0 2002 Published by Elsevier Science Ltd.
Intima Media Thickness and Lipid-lowering Treatment
Table 1. Baseline characteristics of the patients. Values are expressed as mean (SD) unless otherwise stated.
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Carotid and femoral artery IMT measurements and trial design
Patient characteristics No. of patients Age median (range) (years) Gender (M,F) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) No. of current smokers (%) No. of ex-smokers (%) No. of patients on aspirin (%) No. of patients on antihypertensives (%)
25 69 (48–81) 14,11 26.5 (2.8) 145 (10) 87 (8) 5 (20%) 20 (80%) 18 (72%) 20 (80%)
BMI=body mass index.
in patients with peripheral vascular disease (PVD) and raised serum cholesterol 4 and 8 weeks after treatment with atorvastatin. The aim of the study was to establish whether the IMT was significantly changed within this short period.
Methods A total of 25 patients (14 men and 11 women), median age 69 years (range: 48–81) were recruited. Their pretreatment characteristics are shown in Table 1. The study population consisted of patients who were referred to a university hospital vascular surgery clinic with stable PVD and who were found to have a serum cholesterol level [5.5 mmol/l. PVD was defined as stable uncomplicated intermittent claudication with an ankle/brachial pressure index <0.08.
Exclusion criteria Patients with critical leg ischaemia, significant carotid artery disease (>70% stenosis) or previous carotid surgery, diabetes mellitus, poorly controlled hypertension, serum creatinine level above the upper limit of the reference range (120 mol/l) and patients receiving lipid-lowering treatment were excluded.
Blood samples and measurements A fasting (12 h) venous sample was obtained to assess: (1) Lipid profile, (2) haematological and biochemical profile, (3) plasma fibrinogen and factor XII levels (as indices of the coagulation system), and (4) renal and liver function tests.
A variety of IMT measurement protocols, based on different ultrasound methods, have been developed in order to obtain reliable and reproducible results.26 We used an automatic technique,17 that has been validated against the conventional manual technique; there was a significant correlation between the two methods.27 This technique has been described elsewhere in detail;17,27 in brief, patients were scanned in the supine position and electrocardiographic (ECG) leads were placed appropriately on the chest wall for ECG R-wave triggered measurements. A longitudinal B-Mode image of the blood vessel was visualised using a duplex ultrasonography scanner with a 7.5 MHz linear-transducer (Scanner 350, Pie Medical System, Maastricht, The Netherlands), then switched to echo M-mode with a high pulse-repetition frequency and a short activation pulse. The radio frequency (RF) signals were transferred to a computer with wall tracking software and the IMT was determined automatically (WTS ver 2.0, Pie Medical System, Maastricht, The Netherlands).17 The IMT was measured at the posterior wall, because the trailing edge of the adventitia signal of the anterior wall will obscure the media and influence the measurement of this IMT. On the other hand the far wall is well visualised and likely to show the earliest atherosclerotic changes.17 The same locations of arteries were scanned pre-treatment as well as at 4 and 8 weeks after treatment with atorvastatin (Lipitor) 20 mg/day. The IMT measurements were taken 2 cm proximal to the carotid bifurcation. The IMT was expressed as the mean of six measurements taken at each visit; these were blindly analysed. The same method was used for the femoral artery measurements, which were taken 2 cm proximal to the origin of the superficial femoral artery.
Ethics, data collection and statistical analysis The Ethics Committee of the Royal Free Hospital NHS Trust approved the study and written consent was obtained from each patient. The data was blindly analysed by giving random numbers to each measurement of IMT and each blood sample. Paired t-tests were used to check if the changes in IMT (pre-treatment vs 4 weeks and pre-treatment vs 8 weeks) and lipid profile (pre-treatment vs 8 weeks) were significant. The multivariate ANOVA test was used to assess the Eur J Vasc Endovasc Surg Vol 23, April 2002
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Table 2. Changes in serum creatinine, serum urea, serum urate, plasma fibrinogen and plasma factor XII after 8 weeks of treatment with 20 mg/day of atorvastatin. The results are expressed as median and range. Test Serum creatinine (mol/l)
Serum urate (mmol/l)
All patients (n=25) Patients with the highest 12 creatinine values∗ Patients with the lowest 13 creatinine values∗ All patients (n=25) Patients with the highest 12 creatinine values∗ Patients with the lowest 13 creatinine values∗
Urea (mmol/l) Fibrinogen (mg/l) Factor XII (ng/ml)
Pre-treatment
8 weeks
p value
87 (67–114) 98 (89–114)
84 (64–112) 91 (83–112)
0.007 0.008
77 (67–84)
77 (64–85)
NS
0.33 (0.17–0.43) 0.33 (0.24–0.43)
0.32 (0.19–0.40) 0.32 (0.22–0.40)
NS 0.04
0.29 (0.17–0.40)
0.30 (0.19–0.35)
NS
5.7 (1.9–9.6) 323 (216–565) 1.7 (0.7–2.8)
5.4 (1.8–9.1) 304 (194–494) 1.2 (0.7–4.2)
NS NS NS
NS=not significant, ∗ pre-treatment.
trend of changes in IMT over the whole study period (i.e. 8 weeks). The significance of the changes in serum creatinine levels before and after treatment for 8 weeks was assessed using a paired Wilcoxon test. A p value of <0.05 was considered statistically significant. Correlation was assessed by deriving the Pearson’s coefficient. The primary end point was to measure the changes in carotid and femoral IMT after 8 weeks of treatment. Secondary end points were the changes in the other variables measured in the blood.
Table 3. Changes in the lipid profile after 8 weeks treatment with atorvastatin 20 mg/day.
Results
lipoprotein cholesterol (LDL) (p=0.0001). There was no significant change in the HDL level. The triglyceride levels decreased significantly (p=0.05). After 8 weeks treatment all the patients had a LDL level <3.0 mmol/l, the UK guideline value for patients with vascular disease.28
Biochemical results There was no statistical difference in the haematological profile between visits at 0 and 8 weeks (results not shown). There was a significant (p=0.007) decrease in serum creatinine values. The patients were divided into two halves, one with the highest serum creatinine levels (n=12) and the other (n=13) with the lowest serum creatinine levels. The decrease in serum creatinine was only significant (p=0.008) in the “higher creatinine” group. Similarly, there was fall in the serum uric acid value in the group with a higher creatinine. There were no significant changes in liver function tests, creatine kinase, fibrinogen, urea and factor XII levels (Table 2).
Changes in the lipid profile Table 3 summarised the lipid profile data. After 8 weeks of treatment there was a significant reduction in total cholesterol (p=0.0004) and in low density Eur J Vasc Endovasc Surg Vol 23, April 2002
Total cholesterol (mmol/l) LDL (mmol/l) HDL (mmol/l) TG (mmol/l)
Pre-treatment
8 weeks
p value
6.0 (0.3)
4.3 (0.8)
0.0004
3.7 (0.2) 1.8 (0.6) 1.3 (0.4)
2.2 (0.5) 2.0 (0.5) 0.8 (0.3)
0.0001 NS 0.05
LDL=low density lipoprotein cholesterol, HDL=high density lipoprotein cholesterol, TG=triglycerides.
Changes in carotid and femoral IMT The ANOVA test for the trend was significant (p= 0.024) for the CCA-IMT and for the CFA-IMT (p= 0.0003). The changes in CCA-IMT and CFA-IMT were not significant when the pre-treatment and 4-week values were compared. However, they were significant (p=0.01 CCA-IMT; p=0.005 CFA-IMT) when the pretreatment and 8-week values were compared (Table 4). There was no significant correlation between the carotid and the femoral IMT values pre-treatment or at the end of the 8 weeks treatment. A decrease of the CCA-IMT by >0.1 mm was noted in 10 patients (40%) after 4 weeks and in 18 patients (72%) after 8 weeks of treatment. For the CFA-IMT the corresponding figures were 8 (32%) and 19 (76%) patients, respectively (Fig.
Intima Media Thickness and Lipid-lowering Treatment
Table 4. Right common carotid artery (CCA) and right common femoral artery (CFA) IMT before and after treatment with 20 mg/ day atorvastatin. Arteries
Pre-treatment
4WP
8WP
∗p value
CCA-IMT CFA-IMT
0.79 (0.21) 0.83 (0.13)
0.75 (0.22) 0.80 (0.09)
0.64 (0.15) 0.69 (0.14)
0.024 0.0003
∗ ANOVA test for the trend over the 8 week treatment period. 4WP, 4 weeks post-treatment; 8WP, 8 weeks post-treatment. The IMT (mm) is expressed as mean±SD.
1). There was no correlation between the changes in the lipid levels and the IMT.
Side effects There were no side effects, vascular events or dropouts during this 8-week study.
Discussion Achieving U.K. guideline values for LDL (<3.0 mmol/ l) within 8 weeks using atorvastatin (20 mg/day) in patients with PVD was associated with a significant decrease in the CCA-IMT and CFA-IMT. These findings confirm those of our preliminary study where we only assessed the CCA-IMT under similar circumstances.25 We attributed this rapid improvement to anti-inflammatory changes25 because it is unlikely that in this short time span there could be a significant reduction in lipid deposits in the intima and media. Our conclusion is based on the findings of an experimental model of carotid injury. In this model, a decrease in intimal thickening, smooth muscle cell proliferation and infiltration by macrophages was noted after the administration of a statin for 2 weeks.29 Furthermore, there is evidence that atorvastatin can significantly reduce the circulating levels of C-reactive protein in patients with combined hyperlipidaemia after treatment for 6 weeks.30 Improvement in endothelial function is also reported within 1 month of lipid lowering treatment.31,32 Observing a trend as early as 4 weeks after commencing atorvastatin supports the rapidity of the effect of lipid lowering treatment on the IMT. Although the 4-week IMT measurements were not significantly decreased when directly compared with pre-treatment values, they were included as part of the ANOVA analysis. This latter analysis was significant for both the CCA-IMT (p=0.024) and CFA-IMT (p=0.0003). This difference in significance suggests that these
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arteries may not respond at the same rate to lipid lowering. Indeed a greater decrease in the CFA-IMT compared with the CCA-IMT was reported after statin treatment (mainly with pravastatin or simvastatin) for a period of 1 year.33 An alternative explanation is that the CFA-IMT is a more relevant measurement in patients with PVD. Others have proposed that initial lipid-lowering therapy is associated with a greater improvement in the CFA-IMT and CCA-IMT than when this form of treatment was intensified in patients already taking statins.33 The baseline lipid levels were similar in both these treatment groups and the CFAIMT and CCA-IMT were assessed after treatment with statin for 1 year.33 It is important to consider that rapid changes in endothelial function (within as little as 1 month) have been reported.25,31,32 Furthermore, in the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL)34 study there was an unexplained significant (p=0.045) and marked (50%) reduction in strokes in patients with acute coronary syndrome who were treated for 16 weeks with atorvastatin (80 mg/ day). MIRACL was a placebo controlled, double blind, randomised study and it included >3000 patients.34 Clearly there is a need to further investigate the rapid changes in the vasculature that follow lipid lowering treatment. This (unfortunately) should include animal-based studies so as to allow for the extensive histological and functional investigation of several arteries. A decrease in carotid artery IMT with atorvastatin has been previously documented but the time scale was of the order of 12–24 months.35,36 The patients had familial hypercholesterolaemia and the dose of atorvastatin was considerably higher (80 mg/day) compared to what we used in the present study (20 mg/day). The significant (p=0.007) fall in serum creatinine levels was relatively unexpected. However, we assessed that variable on the basis of anecdotal observations in patients with PVD after correcting their dyslipidaemia. We also previously reported similar changes in serum uric acid in dyslipidaemic patients treated with atorvastatin.37 We interpret these findings as indicating an increase in renal perfusion following lipid-lowering treatment. This improvement was most evident (p=0.008) in the 50% of our study population with the highest pre-treatment serum creatinine values. In this context, it is relevant that others have proposed that the improvement in microalbuminuria (and blood pressure) after treatment with statins is related to an increased production of nitric oxide (NO) in the kidney.38 NO is a vasodilator and may well Eur J Vasc Endovasc Surg Vol 23, April 2002
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Fig. 1. Distribution of the common carotid (a) and common femoral (b) IMTs for the three measurements (baseline and after 4 and 8 weeks treatment). The horizontal line represents the mean value. For statistical analysis please see Table 4 and text.
improve renal blood flow.38 It is also of interest that microalbuminuria is associated with an increased carotid IMT.39 A further possible effect of statin treatment is a reduction or stabilisation of plaque in the renal arteries. Localised renal atherosclerosis is probably present to a variable degree in patients with PVD.40 The hypothesis that improved renal blood flow was responsible for our observations requires confirmation Eur J Vasc Endovasc Surg Vol 23, April 2002
in larger placebo-controlled studies with a randomised design. These studies should also include a more detailed assessment of renal function. However, these changes may be restricted to a specific patient population. Our findings have several limitations. Our study was not placebo controlled or randomised and the number of patients was small (n=25). We selected a
Intima Media Thickness and Lipid-lowering Treatment
more homogeneous group of PVD patients by defining several exclusion criteria. However, future studies should also consider further selection; for example by gender. The smoking status is also known to adversely influence the benefit derived from treatment with statins.41 In concordance with some but not all other studies,42 we did not observe a rise in plasma fibrinogen concentration after using atorvastatin. Equally, there was no rise in coagulation factor XII. There is also evidence that statins may differ in their effect on HDL elevation.43 However, in this study there was a nonsignificant 11.1% increase in HDL levels after treatment with atorvastatin (20 mg/day) for 8 weeks. This value is in line with what is expected with other statins.43 In conclusion, there was a rapid and significant decrease in the CCA-IMT and CFA-IMT in patients with PVD treated for 8 weeks with atorvastatin (20 mg/day). The trend for this change was visible after 4 weeks. In the same population there was a significant fall in serum creatinine values. This effect was restricted to the patients with the highest serum creatinines. This subgroup also had a small but significant fall in serum uric acid levels. There is a need to confirm these findings in larger placebo-controlled studies with a double blind randomised design. Our results support the findings of several studies showing a rapid (within a few weeks) improvement in indices of vascular function following the correction of a dyslipidaemia with a statin. On a speculative note the present findings, if confirmed, may provide a method for the rapid assessment of the effectiveness of lipid lowering therapy.
Acknowledgements We thank Pfizer Ltd for providing atorvastatin (Lipitor) and an unrestricted grant. We also thank the vascular studies technologists at the Royal Free Hospital for their help.
References 1 Chambless LE, Heiss G, Folsom AR et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Arteriosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997; 146: 483–494. 2 Schmidt C, Wendelhag I. How can the variability in ultrasound measurement of intima-media thickness be reduced? Studies of interobserver variability in carotid and femoral arteries. Clin Physiol 1999; 19: 45–55. 3 Tang R, Hennig M, Thomasson B et al. Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intimamedia thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2000; 18: 197–201.
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4 Montauban SA, De Lange EE, de Groot E, Ackerstaff RG. An in vivo evaluation of the reproducibility of intima-media thickness measurements of the carotid artery segments using Bmode ultrasound. Ultrasound Med Biol 1999; 25: 323–330. 5 Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of Arterial Disease). Circulation 1999; 100: 951–957. 6 Zanchetti A. Carotid artery wall alterations as intermediate end points. Clin Exper Hypertens 1999; 21: 595–607. 7 O’Leary DH, Polak JF, Kronmal RA et al. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke 1996; 27: 224–231. 8 Sugo A, Nakajima S, Kurata T et al. Ultrasonographic assessment of carotid atherosclerosis emphasizing the variety of intimal-medial thickness and the relationship with coronary risk factors. J Cardiol 1997; 30: 321–329. 9 Hulthe J, Wikstrand J, Emanuelsson H et al. Atherosclerotic changes in the carotid artery bulb as measured by B-mode ultrasound are associated with the extent of coronary atherosclerosis. Stroke 1997; 28: 1189–1194. 10 Mack WJ, LaBree L, Liu C, Selzer RH, Hodis HN. Correlations between measures of atherosclerosis change using carotid ultrasonography and coronary angiography. Atherosclerosis 2000; 150: 371–379. 11 Chambless LE, Folsom AR, Clegg LX et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000; 151: 478–487. 12 Allan PL, Mowbray PI, Lee AJ, Fowkes FG. Relationship between carotid intima-media thickness and symptomatic and asymptomatic peripheral arterial disease. The Edinburgh Artery Study. Stroke 1997; 28: 348–353. 13 Wittekoek ME, de Groot E, Prins MH et al. Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease. Atherosclerosis 1999; 146: 271–279. 14 van den Berkmortel FW, Smilde TJ, Wollersheim H et al. Intima-media thickness of peripheral arteries in asymptomatic cigarette smokers. Atherosclerosis 2000; 150: 397–401. 15 Poredos P, Orehek M, Tratnik E. Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction. Angiology 1999; 50: 201–208. 16 Sidhu PS, Desai SR. A simple and reproducible method for assessing intimal-medial thickness of the common carotid artery. Br J Radiol 1997; 70: 85–89. 17 Willekes C, Brands PJ, Willigers JM, Hoeks AP, Reneman RS. Assessment of local differences in intima media thickness in the human common carotid artery. J Vasc Res 1999; 36: 222–228. 18 Stensland-Bugge E, Bonaa KH, Joakimsen O. Reproducibility of ultrasonographically determined intima-media thickness is dependent on arterial wall thickness. The Tromso Study. Stroke 1997; 28: 1972–1980. 19 Wendelhag I, Liang Q, Gustavsson T, Wikstrand J. A new automated computerized analyzing system simplifies readings and reduces the variability in ultrasound measurement of intimamedia thickness. Stroke 1997; 28: 2195–2200. 20 Papadakis JA, Mikhailidis DP, Winder AF. Lipids and stroke: neglect of a useful preventive measure? Cardiovasc Res 1998; 40: 265–271. 21 Rizos E, Mikhailidis DP. Are high-density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res 2001; 52: 199–207. 22 Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278: 313–321. 23 Hodis HN, Mack WJ, Dunn M et al. Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness. Circulation 1997; 95: 2022–2026. Eur J Vasc Endovasc Surg Vol 23, April 2002
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24 Crouse JR, Byington RP, Bond MG et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries: design features of a clinical trial with carotid atherosclerosis outcome. Controlled Clin Trials 1992; 13: 495–506. 25 Davis M, Atwal AS, Nair DR et al. The effect of short-term lipid lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: a pilot study. Curr Med Res Opin 2000; 16: 198–204. 26 Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review of the carotid and femoral intima-media thickness as ad indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiovasc Res 2002, in press. 27 Willekes C, Hoeks AP, Bots ML et al. Evaluation of off-line automated intima-media thickness detection of the common carotid artery based on M-line signal processing. Ultrasound Med Biol 1999; 25: 57–64. 28 Wood D, Durrington P, Poulter N et al. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 (Suppl. 2): S1–S52. 29 Igarashi M, Takeda Y, Mori S et al. Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth. Br J Pharmacol 1997; 120: 1172–1178. 30 Jialal I, Stein D, Balis D et al. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive Creactive protein levels. Circulation 2001; 103: 1933–1935. 31 O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–1131. 32 Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischaemia and function of the endothelium) trial. Circulation 1999; 99: 3227–3233. 33 Ubels FL, Muntinga JH, van Doormaal JJ, Reitsma WD, Smit AJ. Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics. Atherosclerosis 2001; 154: 155– 161.
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34 Schwartz GG, Olsson AG, Ezekowitz MDD et al. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711–1718. 35 Smilde TJ, van den Berkmortel FW, Wollersheim H et al. The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia. Eur J Clin Invest 2000; 30: 473–480. 36 Smilde TJ, van Wissen S, Wollersheim H et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP). Lancet 2001; 357: 577–581. 37 Kakafika A, Liamis G, Elisaf M, Mikhailidis DP. Effect of atorvastatin on serum creatinine levels. Curr Med Res Opin 2001; 17: 230–231. 38 Tonolo G, Melis MG, Formato M et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest 2000; 30: 980–987. 39 Mykkanen L, Zaccaro DJ, O’Leary DH et al. Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1997; 28: 1710–1716. 40 Farmer CKT, Reidy J, Kaira PA, Cook GJR, Scoble J. Individual kidney function before and after renal angioplasty. Lancet 1998; 352: 288–289. 41 Milionis HJ, Rizos E, Mikhailidis DP. Smoking diminishes the benificial effects of statin: observations from the landmark trials. Angiology 2001; 52: 575–587. 42 Wierzbicki AS, Crook MA, Nair DR, Mikhailidis DP, Winder AF. More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolaemia. Atherosclerosis 2000; 148: 204. 43 Mikhailidis DP, Wierzbicki AS. HDL-cholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin. Curr Med Res Opin 2000; 16: 139–146. Accepted 24 January 2002
The Early Effect of Lipid-lowering Treatment on Carotid and Femoral Intima Media Thickness (IMT)† F. Youssef1, A. M. Seifalian1, I. A. Jagroop2, F. Myint1, D. Baker1, D. P. Mikhailidis2 and G. Hamilton1 1
University Department of Surgery and 2Department of Clinical Biochemistry, Royal Free Hospital NHS Trust and Royal Free and University College Medical School, University College London, London, U.K. Objectives: an increased intima media thickness (IMT) is an early indicator of the atherosclerotic process. We investigated the early effect of atorvastatin on the common carotid artery (CCA) and common femoral artery (CFA) IMT. Methods: the IMT was measured in the CCA and the CFA of hyperlipidaemic patients referred with peripheral vascular disease. The measurements were performed using an automated radio frequency IMT technique pre-treatment and at 4 and 8 weeks post-treatment with 20 mg/day atorvastatin. Results: patients (14 men; 11 women), median age 69 years (range: 48–81) had a CCA-IMT mean (SD) of 0.79 (0.21) mm pre-treatment, 0.75 (0.22) mm after 4 weeks, and 0.64 (0.15) mm after 8 weeks. The ANOVA test was significant (p= 0.024) for the CCA-IMT trend. The corresponding CFA-IMT readings were 0.83 (0.13) mm, 0.80 (0.09) mm and 0.69 (0.14) mm (p=0.0003). After 8 weeks of treatment there was a significant reduction in total cholesterol 6.0 (0.3) to 4.3 (0.8) mmol/l, p=0.0004 and low-density lipoprotein cholesterol 3.7 (0.2) to 2.2 (0.5), p=0.0001. There was a significant decrease in median serum creatinine levels after 8 weeks treatment: 87 mol/l (range 67–114) to 84 mol/l (range: 64–112), p=0.007. Conclusions: cholesterol-lowering with atorvastatin 20 mg/day leads to a decrease in CCA-IMT and CFA-IMT. This difference achieved significance after 8 weeks of treatment, but a trend was visible at 4 weeks. These rapid changes in IMT may be attributable to an anti-inflammatory effect. IMT measurement may be a useful tool to rapidly assess the effect of drug treatment on the atherosclerotic process. Key Words: Atorvastatin; Intima media thickness; Femoral; Carotid; Creatinine; Peripheral vascular disease; Urate.
Introduction The common carotid artery intima media thickness (IMT) (CCA-IMT) can be measured accurately noninvasively.1–5 Furthermore, an increased CCA-IMT is associated with major cardiovascular risk factors and is a powerful predictor of cardiovascular events, particularly those associated with ischaemic heart disease (IHD).6–9 In 133 patients the severity of coronary disease, as shown by coronary angiography, was significantly correlated with the CCA-IMT when measured by ultrasonography.10 Increased CCA-IMT is strongly associated with a risk of stroke11 and small changes in the CCA-IMT were also associated with clinically significant atherosclerosis in the peripheral ∗ Please address all correspondence to: G. Hamilton, Consultant Vascular Surgeon, Vascular Unit, University Department of Surgery, Royal Free Hospital NHS Trust, Pond Street, London NW3 2QG, U.K. † Presented at the XV Annual Meeting of the European Society for Vascular Surgery (ESVS), Switzerland (September 2001) and awarded the prize of the best paper presentation in the junior vascular surgeon session.
arteries.12 There are only a few studies involving the common femoral artery IMT (CFA-IMT). They showed that the combined assessment of the carotid and femoral arterial walls provides a more accurate estimate of the atherosclerotic burden in patients with familial hyperlipidaemia.13 The femoral and carotid IMT was also increased in smokers without other vascular risk factors.14,15 B-mode (two-dimensional) duplex ultrasound is also increasingly used for non-invasive visualisation and monitoring of atherosclerotic changes in the vasculature. Its use in measuring the CCA-IMT is now established as a method.16–19 It can be concluded from these studies that the IMT may represent the sum of the cardiovascular risk in an individual. Therefore, the IMT is expected to be increased in those with established vascular disease. Cholesterol-lowering treatment effectively prevents IHD-related events and strokes20,21 and also significantly reduces overall mortality in patients with established IHD.22 In turn, hyperlipidaemia predisposes to an increased CCA-IMT23 and cholesterollowering treatment causes CCA-IMT regression.24,25 Therefore, we monitored the CCA-IMT and CFA-IMT
1078–5884/02/040358+07 $35.00/0 2002 Published by Elsevier Science Ltd.
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Table 1. Baseline characteristics of the patients. Values are expressed as mean (SD) unless otherwise stated.
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Carotid and femoral artery IMT measurements and trial design
Patient characteristics No. of patients Age median (range) (years) Gender (M,F) BMI (kg/m2) Systolic BP (mmHg) Diastolic BP (mmHg) No. of current smokers (%) No. of ex-smokers (%) No. of patients on aspirin (%) No. of patients on antihypertensives (%)
25 69 (48–81) 14,11 26.5 (2.8) 145 (10) 87 (8) 5 (20%) 20 (80%) 18 (72%) 20 (80%)
BMI=body mass index.
in patients with peripheral vascular disease (PVD) and raised serum cholesterol 4 and 8 weeks after treatment with atorvastatin. The aim of the study was to establish whether the IMT was significantly changed within this short period.
Methods A total of 25 patients (14 men and 11 women), median age 69 years (range: 48–81) were recruited. Their pretreatment characteristics are shown in Table 1. The study population consisted of patients who were referred to a university hospital vascular surgery clinic with stable PVD and who were found to have a serum cholesterol level [5.5 mmol/l. PVD was defined as stable uncomplicated intermittent claudication with an ankle/brachial pressure index <0.08.
Exclusion criteria Patients with critical leg ischaemia, significant carotid artery disease (>70% stenosis) or previous carotid surgery, diabetes mellitus, poorly controlled hypertension, serum creatinine level above the upper limit of the reference range (120 mol/l) and patients receiving lipid-lowering treatment were excluded.
Blood samples and measurements A fasting (12 h) venous sample was obtained to assess: (1) Lipid profile, (2) haematological and biochemical profile, (3) plasma fibrinogen and factor XII levels (as indices of the coagulation system), and (4) renal and liver function tests.
A variety of IMT measurement protocols, based on different ultrasound methods, have been developed in order to obtain reliable and reproducible results.26 We used an automatic technique,17 that has been validated against the conventional manual technique; there was a significant correlation between the two methods.27 This technique has been described elsewhere in detail;17,27 in brief, patients were scanned in the supine position and electrocardiographic (ECG) leads were placed appropriately on the chest wall for ECG R-wave triggered measurements. A longitudinal B-Mode image of the blood vessel was visualised using a duplex ultrasonography scanner with a 7.5 MHz linear-transducer (Scanner 350, Pie Medical System, Maastricht, The Netherlands), then switched to echo M-mode with a high pulse-repetition frequency and a short activation pulse. The radio frequency (RF) signals were transferred to a computer with wall tracking software and the IMT was determined automatically (WTS ver 2.0, Pie Medical System, Maastricht, The Netherlands).17 The IMT was measured at the posterior wall, because the trailing edge of the adventitia signal of the anterior wall will obscure the media and influence the measurement of this IMT. On the other hand the far wall is well visualised and likely to show the earliest atherosclerotic changes.17 The same locations of arteries were scanned pre-treatment as well as at 4 and 8 weeks after treatment with atorvastatin (Lipitor) 20 mg/day. The IMT measurements were taken 2 cm proximal to the carotid bifurcation. The IMT was expressed as the mean of six measurements taken at each visit; these were blindly analysed. The same method was used for the femoral artery measurements, which were taken 2 cm proximal to the origin of the superficial femoral artery.
Ethics, data collection and statistical analysis The Ethics Committee of the Royal Free Hospital NHS Trust approved the study and written consent was obtained from each patient. The data was blindly analysed by giving random numbers to each measurement of IMT and each blood sample. Paired t-tests were used to check if the changes in IMT (pre-treatment vs 4 weeks and pre-treatment vs 8 weeks) and lipid profile (pre-treatment vs 8 weeks) were significant. The multivariate ANOVA test was used to assess the Eur J Vasc Endovasc Surg Vol 23, April 2002
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Table 2. Changes in serum creatinine, serum urea, serum urate, plasma fibrinogen and plasma factor XII after 8 weeks of treatment with 20 mg/day of atorvastatin. The results are expressed as median and range. Test Serum creatinine (mol/l)
Serum urate (mmol/l)
All patients (n=25) Patients with the highest 12 creatinine values∗ Patients with the lowest 13 creatinine values∗ All patients (n=25) Patients with the highest 12 creatinine values∗ Patients with the lowest 13 creatinine values∗
Urea (mmol/l) Fibrinogen (mg/l) Factor XII (ng/ml)
Pre-treatment
8 weeks
p value
87 (67–114) 98 (89–114)
84 (64–112) 91 (83–112)
0.007 0.008
77 (67–84)
77 (64–85)
NS
0.33 (0.17–0.43) 0.33 (0.24–0.43)
0.32 (0.19–0.40) 0.32 (0.22–0.40)
NS 0.04
0.29 (0.17–0.40)
0.30 (0.19–0.35)
NS
5.7 (1.9–9.6) 323 (216–565) 1.7 (0.7–2.8)
5.4 (1.8–9.1) 304 (194–494) 1.2 (0.7–4.2)
NS NS NS
NS=not significant, ∗ pre-treatment.
trend of changes in IMT over the whole study period (i.e. 8 weeks). The significance of the changes in serum creatinine levels before and after treatment for 8 weeks was assessed using a paired Wilcoxon test. A p value of <0.05 was considered statistically significant. Correlation was assessed by deriving the Pearson’s coefficient. The primary end point was to measure the changes in carotid and femoral IMT after 8 weeks of treatment. Secondary end points were the changes in the other variables measured in the blood.
Table 3. Changes in the lipid profile after 8 weeks treatment with atorvastatin 20 mg/day.
Results
lipoprotein cholesterol (LDL) (p=0.0001). There was no significant change in the HDL level. The triglyceride levels decreased significantly (p=0.05). After 8 weeks treatment all the patients had a LDL level <3.0 mmol/l, the UK guideline value for patients with vascular disease.28
Biochemical results There was no statistical difference in the haematological profile between visits at 0 and 8 weeks (results not shown). There was a significant (p=0.007) decrease in serum creatinine values. The patients were divided into two halves, one with the highest serum creatinine levels (n=12) and the other (n=13) with the lowest serum creatinine levels. The decrease in serum creatinine was only significant (p=0.008) in the “higher creatinine” group. Similarly, there was fall in the serum uric acid value in the group with a higher creatinine. There were no significant changes in liver function tests, creatine kinase, fibrinogen, urea and factor XII levels (Table 2).
Changes in the lipid profile Table 3 summarised the lipid profile data. After 8 weeks of treatment there was a significant reduction in total cholesterol (p=0.0004) and in low density Eur J Vasc Endovasc Surg Vol 23, April 2002
Total cholesterol (mmol/l) LDL (mmol/l) HDL (mmol/l) TG (mmol/l)
Pre-treatment
8 weeks
p value
6.0 (0.3)
4.3 (0.8)
0.0004
3.7 (0.2) 1.8 (0.6) 1.3 (0.4)
2.2 (0.5) 2.0 (0.5) 0.8 (0.3)
0.0001 NS 0.05
LDL=low density lipoprotein cholesterol, HDL=high density lipoprotein cholesterol, TG=triglycerides.
Changes in carotid and femoral IMT The ANOVA test for the trend was significant (p= 0.024) for the CCA-IMT and for the CFA-IMT (p= 0.0003). The changes in CCA-IMT and CFA-IMT were not significant when the pre-treatment and 4-week values were compared. However, they were significant (p=0.01 CCA-IMT; p=0.005 CFA-IMT) when the pretreatment and 8-week values were compared (Table 4). There was no significant correlation between the carotid and the femoral IMT values pre-treatment or at the end of the 8 weeks treatment. A decrease of the CCA-IMT by >0.1 mm was noted in 10 patients (40%) after 4 weeks and in 18 patients (72%) after 8 weeks of treatment. For the CFA-IMT the corresponding figures were 8 (32%) and 19 (76%) patients, respectively (Fig.
Intima Media Thickness and Lipid-lowering Treatment
Table 4. Right common carotid artery (CCA) and right common femoral artery (CFA) IMT before and after treatment with 20 mg/ day atorvastatin. Arteries
Pre-treatment
4WP
8WP
∗p value
CCA-IMT CFA-IMT
0.79 (0.21) 0.83 (0.13)
0.75 (0.22) 0.80 (0.09)
0.64 (0.15) 0.69 (0.14)
0.024 0.0003
∗ ANOVA test for the trend over the 8 week treatment period. 4WP, 4 weeks post-treatment; 8WP, 8 weeks post-treatment. The IMT (mm) is expressed as mean±SD.
1). There was no correlation between the changes in the lipid levels and the IMT.
Side effects There were no side effects, vascular events or dropouts during this 8-week study.
Discussion Achieving U.K. guideline values for LDL (<3.0 mmol/ l) within 8 weeks using atorvastatin (20 mg/day) in patients with PVD was associated with a significant decrease in the CCA-IMT and CFA-IMT. These findings confirm those of our preliminary study where we only assessed the CCA-IMT under similar circumstances.25 We attributed this rapid improvement to anti-inflammatory changes25 because it is unlikely that in this short time span there could be a significant reduction in lipid deposits in the intima and media. Our conclusion is based on the findings of an experimental model of carotid injury. In this model, a decrease in intimal thickening, smooth muscle cell proliferation and infiltration by macrophages was noted after the administration of a statin for 2 weeks.29 Furthermore, there is evidence that atorvastatin can significantly reduce the circulating levels of C-reactive protein in patients with combined hyperlipidaemia after treatment for 6 weeks.30 Improvement in endothelial function is also reported within 1 month of lipid lowering treatment.31,32 Observing a trend as early as 4 weeks after commencing atorvastatin supports the rapidity of the effect of lipid lowering treatment on the IMT. Although the 4-week IMT measurements were not significantly decreased when directly compared with pre-treatment values, they were included as part of the ANOVA analysis. This latter analysis was significant for both the CCA-IMT (p=0.024) and CFA-IMT (p=0.0003). This difference in significance suggests that these
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arteries may not respond at the same rate to lipid lowering. Indeed a greater decrease in the CFA-IMT compared with the CCA-IMT was reported after statin treatment (mainly with pravastatin or simvastatin) for a period of 1 year.33 An alternative explanation is that the CFA-IMT is a more relevant measurement in patients with PVD. Others have proposed that initial lipid-lowering therapy is associated with a greater improvement in the CFA-IMT and CCA-IMT than when this form of treatment was intensified in patients already taking statins.33 The baseline lipid levels were similar in both these treatment groups and the CFAIMT and CCA-IMT were assessed after treatment with statin for 1 year.33 It is important to consider that rapid changes in endothelial function (within as little as 1 month) have been reported.25,31,32 Furthermore, in the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL)34 study there was an unexplained significant (p=0.045) and marked (50%) reduction in strokes in patients with acute coronary syndrome who were treated for 16 weeks with atorvastatin (80 mg/ day). MIRACL was a placebo controlled, double blind, randomised study and it included >3000 patients.34 Clearly there is a need to further investigate the rapid changes in the vasculature that follow lipid lowering treatment. This (unfortunately) should include animal-based studies so as to allow for the extensive histological and functional investigation of several arteries. A decrease in carotid artery IMT with atorvastatin has been previously documented but the time scale was of the order of 12–24 months.35,36 The patients had familial hypercholesterolaemia and the dose of atorvastatin was considerably higher (80 mg/day) compared to what we used in the present study (20 mg/day). The significant (p=0.007) fall in serum creatinine levels was relatively unexpected. However, we assessed that variable on the basis of anecdotal observations in patients with PVD after correcting their dyslipidaemia. We also previously reported similar changes in serum uric acid in dyslipidaemic patients treated with atorvastatin.37 We interpret these findings as indicating an increase in renal perfusion following lipid-lowering treatment. This improvement was most evident (p=0.008) in the 50% of our study population with the highest pre-treatment serum creatinine values. In this context, it is relevant that others have proposed that the improvement in microalbuminuria (and blood pressure) after treatment with statins is related to an increased production of nitric oxide (NO) in the kidney.38 NO is a vasodilator and may well Eur J Vasc Endovasc Surg Vol 23, April 2002
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Fig. 1. Distribution of the common carotid (a) and common femoral (b) IMTs for the three measurements (baseline and after 4 and 8 weeks treatment). The horizontal line represents the mean value. For statistical analysis please see Table 4 and text.
improve renal blood flow.38 It is also of interest that microalbuminuria is associated with an increased carotid IMT.39 A further possible effect of statin treatment is a reduction or stabilisation of plaque in the renal arteries. Localised renal atherosclerosis is probably present to a variable degree in patients with PVD.40 The hypothesis that improved renal blood flow was responsible for our observations requires confirmation Eur J Vasc Endovasc Surg Vol 23, April 2002
in larger placebo-controlled studies with a randomised design. These studies should also include a more detailed assessment of renal function. However, these changes may be restricted to a specific patient population. Our findings have several limitations. Our study was not placebo controlled or randomised and the number of patients was small (n=25). We selected a
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more homogeneous group of PVD patients by defining several exclusion criteria. However, future studies should also consider further selection; for example by gender. The smoking status is also known to adversely influence the benefit derived from treatment with statins.41 In concordance with some but not all other studies,42 we did not observe a rise in plasma fibrinogen concentration after using atorvastatin. Equally, there was no rise in coagulation factor XII. There is also evidence that statins may differ in their effect on HDL elevation.43 However, in this study there was a nonsignificant 11.1% increase in HDL levels after treatment with atorvastatin (20 mg/day) for 8 weeks. This value is in line with what is expected with other statins.43 In conclusion, there was a rapid and significant decrease in the CCA-IMT and CFA-IMT in patients with PVD treated for 8 weeks with atorvastatin (20 mg/day). The trend for this change was visible after 4 weeks. In the same population there was a significant fall in serum creatinine values. This effect was restricted to the patients with the highest serum creatinines. This subgroup also had a small but significant fall in serum uric acid levels. There is a need to confirm these findings in larger placebo-controlled studies with a double blind randomised design. Our results support the findings of several studies showing a rapid (within a few weeks) improvement in indices of vascular function following the correction of a dyslipidaemia with a statin. On a speculative note the present findings, if confirmed, may provide a method for the rapid assessment of the effectiveness of lipid lowering therapy.
Acknowledgements We thank Pfizer Ltd for providing atorvastatin (Lipitor) and an unrestricted grant. We also thank the vascular studies technologists at the Royal Free Hospital for their help.
References 1 Chambless LE, Heiss G, Folsom AR et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Arteriosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997; 146: 483–494. 2 Schmidt C, Wendelhag I. How can the variability in ultrasound measurement of intima-media thickness be reduced? Studies of interobserver variability in carotid and femoral arteries. Clin Physiol 1999; 19: 45–55. 3 Tang R, Hennig M, Thomasson B et al. Baseline reproducibility of B-mode ultrasonic measurement of carotid artery intimamedia thickness: the European Lacidipine Study on Atherosclerosis (ELSA). J Hypertens 2000; 18: 197–201.
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4 Montauban SA, De Lange EE, de Groot E, Ackerstaff RG. An in vivo evaluation of the reproducibility of intima-media thickness measurements of the carotid artery segments using Bmode ultrasound. Ultrasound Med Biol 1999; 25: 323–330. 5 Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. Common carotid intima-media thickness and arterial stiffness: indicators of cardiovascular risk in high-risk patients. The SMART Study (Second Manifestations of Arterial Disease). Circulation 1999; 100: 951–957. 6 Zanchetti A. Carotid artery wall alterations as intermediate end points. Clin Exper Hypertens 1999; 21: 595–607. 7 O’Leary DH, Polak JF, Kronmal RA et al. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke 1996; 27: 224–231. 8 Sugo A, Nakajima S, Kurata T et al. Ultrasonographic assessment of carotid atherosclerosis emphasizing the variety of intimal-medial thickness and the relationship with coronary risk factors. J Cardiol 1997; 30: 321–329. 9 Hulthe J, Wikstrand J, Emanuelsson H et al. Atherosclerotic changes in the carotid artery bulb as measured by B-mode ultrasound are associated with the extent of coronary atherosclerosis. Stroke 1997; 28: 1189–1194. 10 Mack WJ, LaBree L, Liu C, Selzer RH, Hodis HN. Correlations between measures of atherosclerosis change using carotid ultrasonography and coronary angiography. Atherosclerosis 2000; 150: 371–379. 11 Chambless LE, Folsom AR, Clegg LX et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000; 151: 478–487. 12 Allan PL, Mowbray PI, Lee AJ, Fowkes FG. Relationship between carotid intima-media thickness and symptomatic and asymptomatic peripheral arterial disease. The Edinburgh Artery Study. Stroke 1997; 28: 348–353. 13 Wittekoek ME, de Groot E, Prins MH et al. Differences in intima-media thickness in the carotid and femoral arteries in familial hypercholesterolemic heterozygotes with and without clinical manifestations of cardiovascular disease. Atherosclerosis 1999; 146: 271–279. 14 van den Berkmortel FW, Smilde TJ, Wollersheim H et al. Intima-media thickness of peripheral arteries in asymptomatic cigarette smokers. Atherosclerosis 2000; 150: 397–401. 15 Poredos P, Orehek M, Tratnik E. Smoking is associated with dose-related increase of intima-media thickness and endothelial dysfunction. Angiology 1999; 50: 201–208. 16 Sidhu PS, Desai SR. A simple and reproducible method for assessing intimal-medial thickness of the common carotid artery. Br J Radiol 1997; 70: 85–89. 17 Willekes C, Brands PJ, Willigers JM, Hoeks AP, Reneman RS. Assessment of local differences in intima media thickness in the human common carotid artery. J Vasc Res 1999; 36: 222–228. 18 Stensland-Bugge E, Bonaa KH, Joakimsen O. Reproducibility of ultrasonographically determined intima-media thickness is dependent on arterial wall thickness. The Tromso Study. Stroke 1997; 28: 1972–1980. 19 Wendelhag I, Liang Q, Gustavsson T, Wikstrand J. A new automated computerized analyzing system simplifies readings and reduces the variability in ultrasound measurement of intimamedia thickness. Stroke 1997; 28: 2195–2200. 20 Papadakis JA, Mikhailidis DP, Winder AF. Lipids and stroke: neglect of a useful preventive measure? Cardiovasc Res 1998; 40: 265–271. 21 Rizos E, Mikhailidis DP. Are high-density lipoprotein (HDL) and triglyceride levels relevant in stroke prevention? Cardiovasc Res 2001; 52: 199–207. 22 Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA 1997; 278: 313–321. 23 Hodis HN, Mack WJ, Dunn M et al. Intermediate-density lipoproteins and progression of carotid arterial wall intima-media thickness. Circulation 1997; 95: 2022–2026. Eur J Vasc Endovasc Surg Vol 23, April 2002
364
F. Youssef et al.
24 Crouse JR, Byington RP, Bond MG et al. Pravastatin, lipids, and atherosclerosis in the carotid arteries: design features of a clinical trial with carotid atherosclerosis outcome. Controlled Clin Trials 1992; 13: 495–506. 25 Davis M, Atwal AS, Nair DR et al. The effect of short-term lipid lowering with atorvastatin on carotid artery intima media thickness in patients with peripheral vascular disease: a pilot study. Curr Med Res Opin 2000; 16: 198–204. 26 Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review of the carotid and femoral intima-media thickness as ad indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiovasc Res 2002, in press. 27 Willekes C, Hoeks AP, Bots ML et al. Evaluation of off-line automated intima-media thickness detection of the common carotid artery based on M-line signal processing. Ultrasound Med Biol 1999; 25: 57–64. 28 Wood D, Durrington P, Poulter N et al. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 (Suppl. 2): S1–S52. 29 Igarashi M, Takeda Y, Mori S et al. Suppression of neointimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth. Br J Pharmacol 1997; 120: 1172–1178. 30 Jialal I, Stein D, Balis D et al. Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive Creactive protein levels. Circulation 2001; 103: 1933–1935. 31 O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMGcoenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 1126–1131. 32 Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischaemia and function of the endothelium) trial. Circulation 1999; 99: 3227–3233. 33 Ubels FL, Muntinga JH, van Doormaal JJ, Reitsma WD, Smit AJ. Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics. Atherosclerosis 2001; 154: 155– 161.
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34 Schwartz GG, Olsson AG, Ezekowitz MDD et al. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001; 285: 1711–1718. 35 Smilde TJ, van den Berkmortel FW, Wollersheim H et al. The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia. Eur J Clin Invest 2000; 30: 473–480. 36 Smilde TJ, van Wissen S, Wollersheim H et al. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP). Lancet 2001; 357: 577–581. 37 Kakafika A, Liamis G, Elisaf M, Mikhailidis DP. Effect of atorvastatin on serum creatinine levels. Curr Med Res Opin 2001; 17: 230–231. 38 Tonolo G, Melis MG, Formato M et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest 2000; 30: 980–987. 39 Mykkanen L, Zaccaro DJ, O’Leary DH et al. Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1997; 28: 1710–1716. 40 Farmer CKT, Reidy J, Kaira PA, Cook GJR, Scoble J. Individual kidney function before and after renal angioplasty. Lancet 1998; 352: 288–289. 41 Milionis HJ, Rizos E, Mikhailidis DP. Smoking diminishes the benificial effects of statin: observations from the landmark trials. Angiology 2001; 52: 575–587. 42 Wierzbicki AS, Crook MA, Nair DR, Mikhailidis DP, Winder AF. More on the effect of atorvastatin on plasma fibrinogen levels in primary hypercholesterolaemia. Atherosclerosis 2000; 148: 204. 43 Mikhailidis DP, Wierzbicki AS. HDL-cholesterol and the treatment of coronary heart disease: contrasting effects of atorvastatin and simvastatin. Curr Med Res Opin 2000; 16: 139–146. Accepted 24 January 2002