(Circulation. 2001;103:1721.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Low-Dose Metoprolol CR/XL and Fluvastatin Slow Progression of Carotid Intima-Media Thickness
Main Results From the ß-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS)
From the Department of Medicine (B.H., G.B.) and the Department of Community Medicine (B.H., L.J.), Malmö University Hospital, Lund University, Lund, Sweden; Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital (J.W.), Gothenburg, Sweden; and Nordic School of Public Health (H.W.), Gothenburg, Sweden. Dr Wikstrand is also senior medical advisor at Clinical Science, AstraZeneca, Mölndal, Sweden.
Correspondence to Professor Göran Berglund, Department of Medicine, Malmö University Hospital, S 205 02 Malmö, Sweden. E-mail Goran.Berglund{at}medforsk.mas.lu.se
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Abstract |
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Background—Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). ß-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT.
Methods and Results—We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMTmax in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (-0.058 mm/y; 95% CI, -0.094 to -0.023; P=0.004; and -0.023 mm/y; 95% CI, -0.044 to -0.003; P=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL–treated patients (5 versus 13 patients, P=0.055). Rate of IMTmean progression in the common carotid at 36 months was reduced by fluvastatin (-0.009 mm/y; 95% CI, -0.015 to -0.003; P=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes.
Conclusions—This is the first randomized trial to show that a ß-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that ß-blockers may have a favorable effect on atherosclerosis development.
Key Words: drugs • ultrasonics • carotid arteries • trials
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Introduction |
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Incidence of cardiovascular events in both secondary1 and primary prevention trials2 has been reduced by statins. It has also been shown that statins can reduce the rate of progression of intima-media thickness (IMT) in the carotid arteries.3 4 5 6 These results have corroborated the hypothesis of the importance of cholesterol in the development of atherosclerosis.7
ß-Blockers have also been shown to reduce cardiovascular events and mortality in secondary8 9 and primary10 prevention studies. In animal studies, ß-blockers reduced the degree of diet-induced11 and stress-induced12 13 atherosclerosis, but no direct evidence of an antiatherosclerotic effect of ß-blockers, similar to the effects of statins on carotid artery IMT, has been shown in humans.
The objective of the placebo-controlled ß-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS) was to compare the effect of low-dose metoprolol CR/XL and fluvastatin on the progression of carotid IMT and incidence of myocardial infarction and stroke during 36 months of treatment in subjects who had carotid plaque but no symptoms of carotid artery disease.
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Methods |
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Study Design
BCAPS was a randomized, double blind, placebo-controlled, single-center clinical trial.
Eligibility
The study population consisted of men and women 49 to
70 years of age with plaque in the right carotid artery but with no
symptoms of carotid artery disease. Recruitment and screening of
participants for the trial were from the Malmö Diet and Cancer
cohort.14 A random 50% of
those who entered the study between November 1991 and February 1994
(n=6103) were invited to take part in a study on the epidemiology of
carotid artery disease15 ;
2585 subjects (44%) had carotid plaque (see definition that follows)
and were invited to participate in the BCAPS trial; 1548 subjects
(60%) came to the enrollment examination (visit 1), which included a
2D B-mode ultrasound of the right carotid artery. Seven hundred
ninety-seven subjects (435 women) accepted , but 4 subjects were
excluded because of protocol violation. None of these subjects had
started any study treatment. All participants (n=793) provided written
informed consent. The Ethics Committee of Lund University approved the
study.
Exclusion Criteria
Exclusion criteria were history of myocardial
infarction, angina pectoris, or stroke within the preceding 3 months;
history of surgical intervention in the right carotid artery; regular
use of ß-blockers or statins; blood pressure >160 (systolic) or 95
(diastolic) mm Hg; total cholesterol >8.0 mmol/L; hyperglycemia
suspected to require insulin treatment; and conditions that in the
opinion of the investigator rendered the subject unsuitable for the
trial.
Randomization
Participants were randomly assigned to 1 of 4 drug
combination groups according to a factorial design: placebo/placebo,
metoprolol CR/XL (25 mg once daily)/placebo, fluvastatin (40 mg once
daily)/placebo, or metoprolol CR/XL (25 mg once daily)/fluvastatin (40
mg once daily).
Outcome Measures
The primary outcome measures were change in mean IMT
(IMTmean) in the common carotid artery
(10-mm-long section) and change in maximum IMT
(IMTmax) in the carotid bulb. Adverse events,
laboratory findings (see below), mortality, and incidence of myocardial
infarction and stroke were closely monitored.
Baseline Examination and Follow-Up
Visits
The first participant was randomized in November
1994, and the 36-month treatment period was completed for all
participants by February 1999. During the first year, visits occurred
after 1, 3, 6, and 12 months and every 6 months thereafter. Weight was
measured every 6 months, and a fasting lipid profile (total
cholesterol, LDL lipoprotein, HDL lipoprotein, and triglycerides) was
determined every year. Liver transaminases (AST, ALT) and creatine
kinase were obtained at every visit during the first year and then
every year thereafter. AST or ALT values 
3 times and creatine kinase
values 10 times the upper limit of normal were considered elevated
during the study. Carotid ultrasound investigation was performed at
baseline and after 18 and 36 months of treatment. Subjects who
developed high serum cholesterol or high triglycerides during the trial
were recommended to follow a low-fat diet, and if evidence of high
cholesterol values persisted, these subjects (n=68) were referred to an
independent specialist of lipid disorders who had no knowledge of the
subject’s randomization assignment. Twenty-two of these subjects were
prescribed open lipid-lowering therapy. Other conditions, such as high
blood pressure, congestive heart failure, or abnormal laboratory values
during the trial, were dealt with in accordance with existing
guidelines. Vital status was obtained for all subjects at study
termination.
The End Point Committee, consisting of 2 independent scientists, validated all clinical end points at the end of the trial. The Data and Safety Monitoring Board, consisting of independent scientists with expertise in fields relevant to BCAPS, regularly monitored toxicity and blinded outcome data.
B-Mode Ultrasound
An Acuson 128 CT system with a 7-MHz transducer
was used. The examination procedure and image analysis, which have been
described
previously,15 16
were performed by specially trained sonographers certified on
completion of an extensive educational program. In brief, the right
carotid bifurcation was scanned within a predefined window comprising 3
cm of the distal common carotid artery, the bifurcation, and 1 cm of
the internal and external carotid arteries for the presence of plaques,
defined as focal IMT >1.2 mm. Thickness of the intima-media complex
was measured in the far wall according to the leading edge principle
with a specially designed, computer-assisted image analyzing system
based on automated detection of the echo structures but with the option
for manual corrections by the
operator.16 Each image was
analyzed without knowledge of the subject’s randomization
group.
Statistical Analyses
From previous
experience,3 it was
anticipated that the annual progression rate of the carotid artery
IMTmean in the placebo group would be 
0.015
mm/y with an SD of 0.030 mm. A sample size of 200 subjects per group,
ie, a total of 800 individuals, was determined, which was based on a
withdrawal rate of 10%, a significance level of 5% (2 sided), a power
of 0.90, and a treatment effect of 75% (fluvastatin) and 30%
(metoprolol CR/XL).
The primary effect variables, changes in IMTmean of the common carotid artery (IMTmeanCCA) and carotid bulb (IMTmaxBulb), were analyzed for each patient in a linear model (in which all IMT values were log transformed). Change in IMT was defined as the 18- and 36-month value, respectively, while simultaneously considering IMT at baseline. That is, 2 models were formulated with IMT values at 18 and 36 months as the dependent variables, including baseline IMT, the time between measurements, and treatment as covariates. The mean square error from the ANCOVA and Student’s t distribution were used in these calculations. In case of missing 36-month data, the last recorded ultrasound measurements after the baseline examination were used.
The trial did not have adequate statistical power to detect
the effects of the combination of fluvastatin and metoprolol CR/XL. In
post hoc analyses, the effect of metoprolol CR/XL was evaluated in
subjects with serum cholesterol 6.5 mmol/L at baseline, as were the
treatment effect on the combined mean of
IMTmeanCCA and IMTmaxBulb
and the effect on the combined end point of all-cause mortality and a
cardiovascular event (time to first event). A 2-tailed value of
P<0.05 was considered
significant.
The log-rank test was used for comparing clinical event rates. All statistical analyses described were performed according to the intention-to-treat principle.
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Results |
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Baseline Characteristics
The randomization yielded well-balanced treatment groups (Table 1
). Mean baseline LDL cholesterol was 4.1
mmol/L. Current medications at baseline or during trial for other
cardiovascular compounds (eg, diuretics, calcium channel blockers, ACE
inhibitors, aspirin, and postmenopausal hormone replacement therapy for
women) were similar in the treatment groups (data not shown). The mean
follow-up time was 35.9 months (range, 8 to 40
months).
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Metabolic and Physiological Effects of
Treatment
Fluvastatin reduced total cholesterol by 13% (95% CI,
-12 to -15) and LDL cholesterol by 23% (95% CI, -21 to -25),
whereas cholesterol levels remained unchanged in the placebo group.
Serum triglycerides increased 20% (95% CI, 15 to 27) in the
metoprolol CR/XL/placebo group, which was not different from the 12%
(95% CI, 6 to 18) change in the placebo/placebo group. No effect of
metoprolol CR/XL or placebo was observed on other metabolic variables.
Compared with the placebo/placebo group, mean heart rate decreased in
the metoprolol CR/XL/placebo group by 2.5 bpm (95% CI, -4.2 to
-0.7; P=0.006), whereas blood
pressure (-1.3 mm Hg; 95% CI, -4.2 to 1.6;
P=0.372) and lumen diameter
(-0.027 mm; 95% CI, -0.110 to 0.055;
P=0.515) were not significantly
changed
(Figure 1).
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Treatment Effect on Carotid IMT
Baseline ultrasound data are given in
Tables 1
and 2. The observed annual
IMTmeanCCA progression rate in the
placebo/placebo group was 0.013±0.053 mm/y. The annual
IMTmax progression rate in the bifurcation in
the placebo/placebo group was 0.089±0.154 mm/y. Fluvastatin but not
metoprolol CR/XL reduced the rate of progression of
IMTmeanCCA compared with placebo after 36 months
of treatment (mean difference between groups, -0.009 mm/y; 95% CI,
-0.015 to -0.003; P=0.002;
Table 3).
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Metoprolol CR/XL but not fluvastatin was effective in
slowing the progression rate of carotid
IMTmaxBulb compared with placebo after 36 months
of treatment (mean difference between groups, -0.023 mm/y; 95% CI,
-0.044 to -0.003; P=0.014;
Table 3). This effect was evident already after 18 months
of treatment (mean difference between groups, -0.058 mm/y; 95% CI,
-0.094 to -0.023; P=0.004).
Metoprolol CR/XL also reduced the progression rate of
IMTmaxBulb after 36 months of treatment in the
subgroup with serum cholesterol 6.5 mmol/L (n=270) at baseline (mean
difference between groups, -0.053 mm/y; 95% CI, -0.087 to
-0.019; P=0.001).
The combined mean of IMTmeanCCA and carotid IMTmaxBulb was significantly reduced after 18 months of treatment by metoprolol CR/XL compared with placebo (mean difference between groups, -0.031 mm/y; 95% CI, -0.050 to -0.001; P=0.002) but not by fluvastatin compared with placebo (mean difference between groups, -0.007 mm/y; 95% CI, -0.026 to 0.001; P=0.476). After 36 months, both metoprolol CR/XL and fluvastatin reduced this composite variable (mean difference for metoprolol CR/XL, -0.012 mm/y; 95% CI, -0.023 to -0.001; P=0.030; for fluvastatin, -0.011 mm/y; 95% CI, -0.022 to -0.001; P=0.034).
In neither the common carotid artery nor the bifurcation was any significant interaction observed; ie, neither an additive nor a synergistic effect could be detected between the metoprolol CR/XL and fluvastatin groups.
Incidence of Clinical Events During
Follow-Up
Of the participants, 18 had a cardiovascular event (1
subject suffered a fatal and 7 had a nonfatal myocardial infarction; 2
died suddenly because of ischemic heart disease; 8 suffered a nonfatal
stroke). The cardiovascular event rate tended to be lower in patients
treated with metoprolol CR/XL compared with patients not treated with
metoprolol CR/XL (5 versus 13 patients,
P=0.055;
Figure 2, top). The corresponding numbers in patients
treated and not treated with fluvastatin were 7 and 11 patients,
respectively (P=0.350). The
combined end point of all-cause mortality and a cardiovascular event
(time to first event) was significantly lower in patients with than
without treatment with metoprolol CR/XL (8 versus 19 patients,
P=0.031; metoprolol CR/XL
group: 4 deaths, 3 myocardial infarctions, and 1 stroke; placebo group:
7, 5, and 7, respectively;
Figure 2, bottom).
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Tolerability
Permanent withdrawal from randomized treatment was 15%
in the metoprolol CR/XL/placebo group, 21% in the fluvastatin/placebo
group, and 23% in the placebo/placebo group. The withdrawal rate in
the group receiving the combination of the 2 drugs was 25%. Compared
with women without corresponding treatment, women receiving treatment
with fluvastatin had an increased frequency of transiently high liver
enzymes (10.2% versus 1.8%,
P<0.001). Incidence of cancer
or minor adverse events did not differ between the treatment
groups.
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Discussion |
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This is the first evidence from a large-scale randomized controlled study to show that a ß-blocker can reduce the rate of progression of carotid IMT in subjects with carotid plaque but with no symptoms of carotid artery disease. The results may indicate favorable effects on early stages of atherosclerosis development. The results also indicated a beneficial effect on the incidence of cardiovascular events and the combined end point of all-cause mortality and a cardiovascular event (time to first event), although the statistical power was low. The effect was achieved in asymptomatic middle-aged men and women and with a very low dose of metoprolol CR/XL (25 mg once daily) that did not decrease blood pressure. The results may point to an important role of the autonomic nervous system in atherosclerosis development in otherwise healthy people with carotid plaque.
Study Group
The treatment groups were recruited from a screening of
the general population as part of a large-scale screening procedure in
a diet/health
project.14 15 At
51 to 55 years of age, almost 35% of the participants had plaque; at
61 to 65 years of age, 56% were found to have
plaque.15 The background
population to which the findings in this trial can be generalized is
thus very large.
Ultrasound Findings
The increase of IMTmeanCCA in
the placebo/placebo group of BCAPS (0.013 mm/y) is of the same order as
findings in some other major studies that used the ultrasound
technique3 4 in
which progression rates in the placebo/placebo group varied from 0.006
to 0.030 mm/y. The progression rate for IMTmax
in the bifurcation (bulb) in the BCAPS placebo/placebo group (0.089
mm/y) is also comparable to the progression rate in the Pravastatin,
Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II) study
(0.100 mm/y).4
Metoprolol CR/XL 25 mg once daily was effective in slowing the progression of IMTmax in the bifurcation, whereas no significant effect was seen on IMT measurements in the common carotid artery. Fluvastatin, on the other hand, slowed progression in the common carotid, but not to a significant extent in the bifurcation. However, after 3 years of follow-up, the combined mean of IMTmeanCCA and IMTmaxBulb was significantly reduced by both metoprolol CR/XL and fluvastatin. In the Effect on Long-term treatment of metoprolol CR/XL on surrogate Variables for Atherosclerosis disease (ELVA) study (a 3-year randomized study by O. Wiklund, MD, PhD, et al, on the effect of metoprolol CR/XL on carotid IMT in subjects with hypercholesterolemia that has been submitted for publication), a significant effect of metoprolol CR/XL was observed in the common carotid artery. That study, in contrast to BCAPS, included only patients with hypercholesterolemia and used 100 mg instead of 25 mg metoprolol CR/XL. The finding that fluvastatin reduced the progression rate of IMTmeanCCA corroborates the results of several earlier trials evaluating the effect of statins on IMT in the common carotid artery.3 4 5 6 In 1 study,6 a statin was also shown to slow progression of the bifurcation measurement. Different intervention effects of statins and ß-blockers in different parts of the arterial tree cannot be excluded, and it may be that the pathophysiological mechanisms involved in the development of atherosclerosis might differ between straight arterial parts and bifurcations.
Further studies are needed to investigate the dose-dependent effects of metoprolol CR/XL in different arterial regions. However, we find it highly interesting that a dose as low as 25 mg metoprolol CR/XL once daily, a dose very seldom used to treat hypertension or angina pectoris, has an effect on carotid artery IMT. This illustrates the importance of the autonomic nervous system in the pathophysiology of atherosclerosis development. Stress-induced, sympathetic nervous system–mediated adhesion of platelets in bifurcations and atherosclerosis development have been shown in animal studies to be prevented by ß-blocker treatment.11 12 13 17 18 Furthermore, ß-blockers have been shown to increase the production of prostacyclin in animals,19 which may be another factor of importance for the antiatherosclerotic effect observed after ß-blocker treatment. Studies in humans suggest that atherosclerotic lesions are predominantly localized at sites of low shear stress20 21 22 in regions with nonlaminar, low flow with recirculation and stagnant flow zones. One might speculate that these flow disturbances may be lessened by ß-blocker treatment.22 We observed no significant change in carotid artery lumen diameter, indicating that vasodilatation was not responsible for the observed effect of metoprolol CR/XL.
Clinical Implications
The findings of an antiatherosclerotic effect of
metoprolol CR/XL extend the knowledge of the beneficial effects of
ß-blockers. The evidence of a clinical benefit of ß-blockers in
primary and secondary prevention of patients with
hypertension,10 previous
myocardial infarction,8 and
heart failure9 is extended in
this study to middle-aged subjects with plaque in the carotid
bifurcation. The strength of the evidence of a reduction in clinical
events in the present study should not be exaggerated, but the finding
takes on additional meaning because of the large body of evidence of a
cardioprotective effect of ß-blockers in the studies cited
here.8 9 10
However, it should be pointed out that the study group in BCAPS has a
relatively low cardiovascular risk (ie, hypertensives and patients with
total cholesterol >8.0 mmol/L were excluded).
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Conclusions
The results from the BCAP study provide the first evidence in humans that a ß-blocker can slow progression of carotid IMT. The results may indicate favorable effects on early stages of atherosclerosis development. The possible different intervention effects of statins and ß-blockers on atherosclerosis development need further exploration.
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Acknowledgments |
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This study was supported by grants from Astra-Zeneca Pharmaceuticals, Mölndal, Sweden. Members of the Independent End Point Committee were Ola Samuelsson (chairman) and Björn Fagerberg. Members of the Independent Data and Safety Committee were Curt Furberg (chairman), Juukka Salonen, and Diedrich Grobbee. The BCAP study group recognizes that without the time and dedicated effort of all patients and the supporting staff, this study would never have been accomplished.
Received October 3, 2000; revision received December 15, 2000; accepted December 19, 2000.
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References |
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 I. Sipahi, E. M. Tuzcu, K. E. Wolski, S. J. Nicholls, P. Schoenhagen, B. Hu, C. Balog, M. Shishehbor, W. A. Magyar, T. D. Crowe, et al. {beta}-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials Ann Intern Med, July 3, 2007; 147(1): 10 - 18. [Abstract] [Full Text] [PDF]
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 G. Ostling, B. Hedblad, G. Berglund, and I. Goncalves Increased Echolucency of Carotid Plaques in Patients With Type 2 Diabetes Stroke, July 1, 2007; 38(7): 2074 - 2078. [Abstract] [Full Text] [PDF]
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 Authors/Task Force Members:, G. Mancia, G. De Backer, A. Dominiczak, R. Cifkova, R. Fagard, G. Germano, G. Grassi, A. M. Heagerty, S. E. Kjeldsen, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) Eur. Heart J., June 11, 2007; (2007) ehm236v1. [Full Text] [PDF]
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H T Ong beta blockers in hypertension and cardiovascular disease BMJ, May 5, 2007; 334(7600): 946 - 949. [Full Text] [PDF]
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 E.J. Lee, H.J. Kim, J.M. Bae, J.C. Kim, H.J. Han, C.S. Park, N.H. Park, M.S. Kim, and J.A. Ryu Relevance of Common Carotid Intima-Media Thickness and Carotid Plaque as Risk Factors for Ischemic Stroke in Patients with Type 2 Diabetes Mellitus AJNR Am. J. Neuroradiol., May 1, 2007; 28(5): 916 - 919. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, J.-A. Nilsson, A. Schiopu, P. K. Shah, and J. Nilsson Association Between IgM Against an Aldehyde-Modified Peptide in Apolipoprotein B-100 and Progression of Carotid Disease Stroke, May 1, 2007; 38(5): 1495 - 1500. [Abstract] [Full Text] [PDF]
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 J. H. Revkin, C. L. Shear, H. G. Pouleur, S. W. Ryder, and D. G. Orloff Biomarkers in the Prevention and Treatment of Atherosclerosis: Need, Validation, and Future Pharmacol. Rev., March 1, 2007; 59(1): 40 - 53. [Abstract] [Full Text] [PDF]
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V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Circulation, December 19, 2006; 114(25): 2850 - 2870. [Full Text] [PDF]
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 P. M. Nilsson, G. Engstrom, B. Hedblad, J. Frystyk, M. M. Persson, G. Berglund, and A. Flyvbjerg Plasma Adiponectin Levels in Relation to Carotid Intima Media Thickness and Markers of Insulin Resistance Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2758 - 2762. [Abstract] [Full Text] [PDF]
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 S. Zhu, G. Su, and Q. H. Meng Inhibitory Effects of Micronized Fenofibrate on Carotid Atherosclerosis in Patients with Essential Hypertension Clin. Chem., November 1, 2006; 52(11): 2036 - 2042. [Abstract] [Full Text] [PDF]
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 G. N. Fredrikson, G. Berglund, R. Alm, J.-A. Nilsson, P. K. Shah, and J. Nilsson Identification of autoantibodies in human plasma recognizing an apoB-100 LDL receptor binding site peptide J. Lipid Res., September 1, 2006; 47(9): 2049 - 2054. [Abstract] [Full Text] [PDF]
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J.-C. Tardif and C. Berry From coronary artery disease to heart failure: potential benefits of ivabradine Eur. Heart J. Suppl., September 1, 2006; 8(suppl_D): D24 - D29. [Abstract] [Full Text] [PDF]
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J. R. Crouse III Thematic review series: Patient-Oriented Research. Imaging atherosclerosis: state of the art J. Lipid Res., August 1, 2006; 47(8): 1677 - 1699. [Abstract] [Full Text] [PDF]
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J.-G. Wang, J. A. Staessen, Y. Li, L. M. Van Bortel, T. Nawrot, R. Fagard, F. H. Messerli, and M. Safar Carotid Intima-Media Thickness and Antihypertensive Treatment: A Meta-Analysis of Randomized Controlled Trials Stroke, July 1, 2006; 37(7): 1933 - 1940. [Abstract] [Full Text] [PDF]
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A. S. Go, C. Iribarren, M. Chandra, P. V. Lathon, S. P. Fortmann, T. Quertermous, M. A. Hlatky, and for the Atherosclerotic Disease, Vascular Function Statin and beta-blocker therapy and the initial presentation of coronary heart disease. Ann Intern Med, February 21, 2006; 144(4): 229 - 238. [Abstract] [Full Text] [PDF]
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S. C. Smith Jr Can preventive therapy alter the initial presentation of coronary heart disease? Ann Intern Med, February 21, 2006; 144(4): 296 - 297. [Full Text] [PDF]
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 J.-P. Baguet, L. Hammer, P. Levy, H. Pierre, S. Launois, J.-M. Mallion, and J.-L. Pepin The Severity of Oxygen Desaturation Is Predictive of Carotid Wall Thickening and Plaque Occurrence Chest, November 1, 2005; 128(5): 3407 - 3412. [Abstract] [Full Text] [PDF]
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 P. Raggi, A. Bellasi, and C. Ratti Ischemia Imaging and Plaque Imaging in Diabetes: Complementary tools to improve cardiovascular risk management Diabetes Care, November 1, 2005; 28(11): 2787 - 2794. [Abstract] [Full Text] [PDF]
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M.R. Langenfeld, T. Forst, C. Hohberg, P. Kann, G. Lubben, T. Konrad, S.D. Fullert, C. Sachara, and A. Pfutzner Pioglitazone Decreases Carotid Intima-Media Thickness Independently of Glycemic Control in Patients With Type 2 Diabetes Mellitus: Results From a Controlled Randomized Study Circulation, May 17, 2005; 111(19): 2525 - 2531. [Abstract] [Full Text] [PDF]
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A. Diaz, M. G. Bourassa, M.-C. Guertin, and J.-C. Tardif Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease Eur. Heart J., May 2, 2005; 26(10): 967 - 974. [Abstract] [Full Text] [PDF]
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A. Zanchetti, G. Crepaldi, M. G. Bond, G. Gallus, F. Veglia, G. Mancia, A. Ventura, G. Baggio, L. Sampieri, P. Rubba, et al. Different Effects of Antihypertensive Regimens Based on Fosinopril or Hydrochlorothiazide With or Without Lipid Lowering by Pravastatin on Progression of Asymptomatic Carotid Atherosclerosis: Principal Results of PHYLLIS--A Randomized Double-Blind Trial Stroke, December 1, 2004; 35(12): 2807 - 2812. [Abstract] [Full Text] [PDF]
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Task Force Members, J. Lopez-Sendo, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on {beta}-adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society of Cardiology Eur. Heart J., August 1, 2004; 25(15): 1341 - 1362. [Full Text] [PDF]
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B Ohlin, P.M Nilsson, J-A Nilsson, and G Berglund Chronic psychosocial stress predicts long-term cardiovascular morbidity and mortality in middle-aged men Eur. Heart J., May 2, 2004; 25(10): 867 - 873. [Abstract] [Full Text] [PDF]
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A. Scuteri, S. S. Najjar, D. C. Muller, R. Andres, H. Hougaku, E. J. Metter, and E. G. Lakatta Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1388 - 1395. [Abstract] [Full Text] [PDF]
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 J. E Macioch, C D. Katsamakis, J. Robin, P. R Liebson, P. M Meyer, C. Geohas, J. S Raichlen, M. H Davidson, and S. B Feinstein Effect of contrast enhancement on measurement of carotid artery intimal medial thickness Vascular Medicine, February 1, 2004; 9(1): 7 - 12. [Abstract] [PDF]
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P. Poredos Intima-media thickness: indicator of cardiovascular risk and measure of the extent of atherosclerosis Vascular Medicine, February 1, 2004; 9(1): 46 - 54. [Abstract] [PDF]
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M. L. Bots, G. W. Evans, W. A. Riley, and D. E. Grobbee Carotid Intima-Media Thickness Measurements in Intervention Studies: Design Options, Progression Rates, and Sample Size Considerations: A Point of View Stroke, December 1, 2003; 34(12): 2985 - 2994. [Abstract] [Full Text] [PDF]
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J.-C. Tardif, J. Gregoire, P.L. Lallier, and M. Joyal Chronic heart rate reduction with ivabradine and prevention of atherosclerosis progression assessed using intravascular ultrasound Eur. Heart J. Suppl., September 1, 2003; 5(suppl_G): G46 - G51. [Abstract] [PDF]
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L. E. Wagenknecht, D. Zaccaro, M. A. Espeland, A. J. Karter, D. H. O'Leary, and S. M. Haffner Diabetes and Progression of Carotid Atherosclerosis: The Insulin Resistance Atherosclerosis Study Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1035 - 1041. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, M. Ares, B. Cercek, K.-Y. Chyu, P. K. Shah, and J. Nilsson Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 872 - 878. [Abstract] [Full Text] [PDF]
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E. G. Lakatta and D. Levy Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises: Part I: Aging Arteries: A "Set Up" for Vascular Disease Circulation, January 7, 2003; 107(1): 139 - 146. [Full Text] [PDF]
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A. Zanchetti, M. G. Bond, M. Hennig, A. Neiss, G. Mancia, C. Dal Palu, L. Hansson, B. Magnani, K.-H. Rahn, J. L. Reid, et al. Calcium Antagonist Lacidipine Slows Down Progression of Asymptomatic Carotid Atherosclerosis: Principal Results of the European Lacidipine Study on Atherosclerosis (ELSA), a Randomized, Double-Blind, Long-Term Trial Circulation, November 5, 2002; 106(19): 2422 - 2427. [Abstract] [Full Text] [PDF]
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A. J. Taylor, S. M. Kent, P. J. Flaherty, L. C. Coyle, T. T. Markwood, and M. N. Vernalis ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: A Randomized Trial Comparing the Effects of Atorvastatin and Pravastatin on Carotid Intima Medial Thickness Circulation, October 15, 2002; 106(16): 2055 - 2060. [Abstract] [Full Text] [PDF]
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J. R. Crouse III, R. Tang, M. A. Espeland, J. G. Terry, T. Morgan, and M. Mercuri Associations of Extracranial Carotid Atherosclerosis Progression With Coronary Status and Risk Factors in Patients With and Without Coronary Artery Disease Circulation, October 15, 2002; 106(16): 2061 - 2066. [Abstract] [Full Text] [PDF]
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M. Gheorghiade and S. Goldstein {beta}-Blockers in the Post-Myocardial Infarction Patient Circulation, July 23, 2002; 106(4): 394 - 398. [Full Text] [PDF]
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K.-S. Cheng, D. P. Mikhailidis, G. Hamilton, and A. M. Seifalian A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors Cardiovasc Res, June 1, 2002; 54(3): 528 - 538. [Abstract] [Full Text] [PDF]
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O. Wiklund, J. Hulthe, J. Wikstrand, C. Schmidt, S.-O. Olofsson, and G. Bondjers Effect of Controlled Release/Extended Release Metoprolol on Carotid Intima-Media Thickness in Patients With Hypercholesterolemia: A 3-Year Randomized Study Stroke, February 1, 2002; 33(2): 572 - 577. [Abstract] [Full Text] [PDF]
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 B. M. Curtis and J. H. O'Keefe Jr Autonomic Tone as a Cardiovascular Risk Factor: The Dangers of Chronic Fight or Flight Mayo Clin. Proc., January 1, 2002; 77(1): 45 - 54. [Abstract] [PDF]
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J. D. Barth, A. Iglesias del Sol, D. E. Grobbee, J. C.M. Witteman, and M. L. Bots IMT for the Elderly? Stroke, October 1, 2001; 32(10): 2443 - 2445. [Full Text] [PDF]
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