Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: The Carotid Atherosclerosis Italian Ultrasound Study

doi:10.1016/S0002-9343(96)00333-6

The American Journal of Medicine

Volume 101, Issue 6, December 1996, Pages 627-634

https://doi.org/10.1016/S0002-9343(96)00333-6 Get rights and content

Purpose

The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effects of lipid lowering on the progression of carotid intima-media thickness (IMT) in 305 asymptomatic patients from a Mediterranean country.

Patients and methods

Eligibility included hypercholesterolemia (baseline means: low-density lipoprotein [LDL] = 4.68 mmol/L. high-density lipoprotein [HDL] = 1.37 mmol/L), and at least one 1.3 < IMT < 3.5 mm in the carotid arteries. Patients (mean age 55 years, 53% male) were assigned to pravastatin (40 mg/day, n = 151) or placebo (n ≠ 154). Ultrasound imaging was used to quantify IMT at baseline, and semiannually thereafter for up to 3 years. The mean of the 12 maximum IMTs (MMaxIMT), was calculated for each patient visit, and used to determine each patient's longitudinal progression slope. The intention-to-treat group difference in the MMaxIMT progression was chosen a priori as the primary end point.

Results

Five serious cardiovascular events (1 fatal myocardial infarction), and 7 drop-outs for cancer were registered. In the pravastatin group, LDL decreased −0.22 after 3 months versus −0.01 in the placebo group, and remained substantially unchanged afterward (−0.23 versus +0.01 at 36 months, respectively). Progression of the MMaxIMT was 0.009 ± 0.0027 versus −0.0043 ± 0.0028 mm/year ( ± SE, P <0.0007) in the placebo and pravastatin groups, respectively. IMT progression slopes diverged after 6 months of treatment.

Conclusions

Pravastatin stops the progression of carotid IMT in asymptomatic, moderately hypercholesterolemic men and women. This finding extends the beneficial effects of cholesterol lowering to the primary prevention of atherosclerosis in a population with relatively low cardiovascular event rates, and suggests that this benefit is mediated by specific morphological effects on early stages of plaque development.

References (31)

CrouseJR et al.
Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLACII)
Am J Cardiol
(1995)
WattsGF et al.
Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St. Thomas' Atherosclerosis Regression Study (STARS)
Lancet
(1992)
HolmeI et al.
Risk factors and raised atherosclerotic lesions in coronary and cerebral arteries
Arteriosclerosis
(1981)
HertzerNR et al.
Coronary angiography in 506 pa-tients with extracranial cerebrovascular disease
Arch Intern Med
(1985)
RubensJ et al.
Individual susceptibility to extracranial carotid atherosclerosis
Arteriosclerosis
(1988)
CravenTE et al.
Evaluation of the association between carotid artery atherosclerosis and coronary artery atherosclerosis
Stroke
(1990)
HerringtonDM et al.
Strong correlation between carotid artery wall thickness and quantitative coronary artery angiography assessment of coronary atherosclerosis
Circulation
(1994)
PignoliP et al.
Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging
Circulation
(1986)
MercuriM
Noninvasive imaging protocols to detect and monitor carotid atherosclerosis progression
Am J Hypertens
(1994)
ARICInvestigators
The Atherosclerosis Risk in Communities (ARIC) study: design and objectives
Am J Epidemiol
(1989)

O'LearyDH et al.

On behalf of the CHS Collaborative Research Group. Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study

Stroke

(1991)

SalonenJT et al.

Risk factors for carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factors Study

Ann Med

(1989)

BotsML et al.

Cardiovascular determinants of carotid artery disease. The Rotterdam Study

Hypertension

(1992)

SirtoriCR et al.

Pravastatin intervention trial on carotid artery atherosclerosis in patients with mild hypercholesterolemia: the CAIUS study

Int J Cardiac Imag

(1995)

Cited by (254)

Effect of new statin treatment on carotid artery intima-media thickness: A real-life observational study over 10 years
2020, Atherosclerosis
Randomized clinical trials (RCT) have shown statin treatment to slow down the increase in carotid artery intima-media thickness (IMT) seen with ageing. However, those RCTs usually have a limited follow-up (1–3 years). Here an observational study was used to investigate the real-life effect of new statin treatment over a 10-year follow-up.
In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 954 individuals all aged 70 years at baseline were investigated regarding carotid artery IMT three times during 10 years (n = 771 at age 75, and n = 591 at age 80).
At age 70, 503 subjects were statin-naïve and did not receive statin during the 10-year follow-up period (the never-statin group), while 197 subjects were statin-naïve but received statins during the follow-up period (the received-statin group). Low-density lipoprotein (LDL)-cholesterol increased over time in the never-statin group (+0.1 mmol/l, p = 0.0012), but decreased in the group receiving statin treatment (−1.1 mmol/l, p < 0.0001). The never-statin group increased significantly in IMT over the 10 years (+0.07 mm, p < 0.0001), while the numerical increase seen in the received-statin group was not significant (+0.02 mm, p = 0.22) A significant difference in the change in IMT over time was seen between the received-statin group and the never-statin group (p < 0.0001 for interaction between time and group, adjusted for a propensity score).
This real-life observational study showed that new statin treatment reduced the increase in IMT seen over 10 years compared to subjects not treated with statins.
The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study: Rationale and Trial Protocol
2017, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
The primary outcome is change in IMT during 5 years of observation. Based on data from the Carotid Atherosclerosis Italian Ultrasound Study and the Long-term Intervention with Pravastatin in Ischemic Disease trial,7,8 it is assumed that, over a 3- to 5-year period, the maximum IMT will decrease by .013-.014 mm in the pravastatin group and increase by .031-.048 mm in the control group. On the basis of these data, we assumed that a difference of mean in maximum IMT between the 2 groups at 5 years would be .04 mm, with a standard deviation of .17 mm.
The preventive effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study aims to determine the effect of pravastatin on carotid IMT in Japanese patients with hyperlipidemia who developed noncardioembolic ischemic stroke.
This is a substudy of the J-STARS, a multicenter, randomized, open-label, blinded-end point, parallel-group trial to examine whether pravastatin reduces stroke recurrence in patients with noncardioembolic stroke. The patients are randomized to receive pravastatin (10 mg daily) or not to receive any statins. Carotid ultrasonography is performed by well-trained certified examiners in each participating institute, and the recorded data are measured centrally. The primary outcome is change in the IMT of the distal wall in a consecutive 2-cm section on the central side of the common carotid artery bifurcation over 5 years of observation.
The trial may help determine if the usual dose of pravastatin for daily clinical practice in Japan can affect carotid IMT in Japanese patients with noncardioembolic stroke.
Time-related trends in variability of cIMT changes in statin trials
2016, Data in Brief
This brief article provides complementary data supporting the results reported in “Changing Characteristics of Statin-related cIMT Trials from 1988 to 2006” [1]. That article described time-related trends in baseline factors and study characteristics that may have influenced the variability of carotid intima media thickness (cIMT) endpoints (mean of mean and maximum common carotid artery [CCA]/cIMT) in published statin trials. In this brief report, additional details for the studies included in the analysis, and further supporting data, including mean of the maximum CCA/cIMT changes and subgroup data (mean and maximum CCA/cIMT) are provided. For the analysis, study-level data was extracted from 17 statin cIMT trials conducted during 1988–2006, selected on the basis of having at least one statin monotherapy arm in the absence of mixed therapy, and baseline- and study-end values for mean mean and mean maximum CCA/cIMT endpoints. The baseline mean CCA/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Interestingly, all 8 studies conducted before 2000 were significant for cIMT change in which patients did not receive prior LLT; whereas after 2000, the results were more variable and in 4 of 6 trials that did not show a significant cIMT change, patients had received prior treatment. Baseline mean maximum cIMT and LDL-C levels, and annualized changes in studies conducted before 2000 were higher than those conducted after 2000, similar to the results reported in the original article for the mean mean cIMT endpoint. These findings were consistent across study populations of patients with CHD risk versus those without, and in studies with greater LDL-C reductions and with thickened baseline cIMT at study entry for both mean and maximum cIMT changes. Taken together, these results are consistent with trends in recent years toward greater use of lipid-lowering therapy and control of LDL-C that may have impacted the variability in the results of cIMT studies.
Changing characteristics of statin-related cIMT trials from 1988 to 2006
2016, Atherosclerosis
Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed.
This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988–2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed.
Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (−0.0119 mm/year) than after 2000 (−0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (≥2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar.
Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies.
A systematic review of statin-induced muscle problems in clinical trials
2014, American Heart Journal
Statin therapy is associated with muscle problems in approximately 10% to 25% of patients treated in clinical practice, but muscle problems have rarely been reported in controlled clinical trials. We performed a systematic search and review of statin clinical trials to examine how these studies evaluated muscle problems and to determine why there are apparent differences in muscle problems between clinical trials and practice. We initially identified 1,012 reports related to clinical trials of statin therapy, 42 of which qualified for analysis. Fifteen, 4, and 22 trials reported creatine kinase values only >10, 5, and 3 times the upper limits of normal, respectively, in both statin- and placebo-treated participants. Four trials reported average creatine kinase values, which increased with statin treatment in 3 instances. Twenty-six trials reported muscle problems, with an average incidence in statin- and placebo-treated participants of 13%, but only one trial specifically queried about muscle problems. Three trials used a run-in period to eliminate participants with statin intolerance and noncompliance. The percentage of muscle problems tended to be higher with statin treatment (12.7%) than with placebo group (12.4%, P = .06). This small difference probably reflects a high background rate of nonspecific muscle problems in both groups that could not be distinguished from statin-associated myalgia because most clinical trials did not use a standard definition for statin myalgia.
A systematic review of the time course of atherosclerotic plaque regression
2014, Atherosclerosis
Citation Excerpt :
Studies showing less progression had an average LDL-C reduction of 19.1% from baseline, though 4 [13,19,20] of the 7 studies did not report data on LDL-C reductions. A total of 22 trials were analyzed, 10 trials showed plaque regression [10,11,23–30], 4 showed significant slowing of progression [18–20], and 5 demonstrated no effect when compared to a control group [31–34,36]. The studies examining CIMT (n = 18) were an average of 25.6 months in duration.
We sought to determine the time required for lipid treatment to produce regression of atherosclerotic plaques.
The cholesterol content of atherosclerotic plaques contributes to their instability, and most acute cardiac events including myocardial infarction and sudden death are produced by coronary plaque disruption. We systematically reviewed the literature on atherosclerosis regression to identify the time required for cholesterol egress, plaque regression, and possible plaque stabilization. Such information may help decide when patients with statin side effects or other reasons for statin discontinuation could consider a reduction in the intensity of treatment.
We performed a PubMed search to identify English language articles reporting atherosclerotic regression. Articles pertinent to the topic were reviewed in detail.
We identified 189 articles, 50 of which provided sufficient information to establish a rate of regression and 31 of which demonstrated plaque regression with statin therapy in the carotid (n = 11), coronary (n = 16), and aortic (n = 4) vascular beds. Plaque regression occurred after an average of 19.7 months of treatment.
Regression of atherosclerotic plaque using statin therapy in those studies documenting regression occurred after an average time of 19.7 months. This suggests that patients should undergo approximately two years of aggressive lipid reduction before considering a reduction of statin therapy.

View all citing articles on Scopus

^*: CAIUS was funded through independent research grants provided by Bristol-Myers Squibb S.p.A. Italy, and in part by a grant from the Italian National Research Council (C.N.R. Progetto Finalizzato, Invecchiamento, SP321).

^†: Prof. Giancario Descovich is deceased.

View full text

Clinical studyPravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: The Carotid Atherosclerosis Italian Ultrasound Study*

Purpose

Patients and methods

Results

Conclusions

Am J Cardiol

Lancet

Risk factors and raised atherosclerotic lesions in coronary and cerebral arteries

Arteriosclerosis

Coronary angiography in 506 pa-tients with extracranial cerebrovascular disease

Arch Intern Med

Individual susceptibility to extracranial carotid atherosclerosis

Arteriosclerosis

Evaluation of the association between carotid artery atherosclerosis and coronary artery atherosclerosis

Stroke

Strong correlation between carotid artery wall thickness and quantitative coronary artery angiography assessment of coronary atherosclerosis

Circulation

Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging

Circulation

Noninvasive imaging protocols to detect and monitor carotid atherosclerosis progression

Am J Hypertens

The Atherosclerosis Risk in Communities (ARIC) study: design and objectives

Am J Epidemiol

On behalf of the CHS Collaborative Research Group. Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study

Stroke

Risk factors for carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factors Study

Ann Med

Cardiovascular determinants of carotid artery disease. The Rotterdam Study

Hypertension

Pravastatin intervention trial on carotid artery atherosclerosis in patients with mild hypercholesterolemia: the CAIUS study

Int J Cardiac Imag

Clinical study
Pravastatin reduces carotid intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: The Carotid Atherosclerosis Italian Ultrasound Study*