(Circulation. 2000;102:1503.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Effect of Amlodipine on the Progression of Atherosclerosis and the Occurrence of Clinical Events
From the University of Michigan Medical Center (B.P.); Wake Forest University School of Medicine (R.P.B., C.D.F., M.E.M., W.R.); University of Minnesota Hospital/Clinic (D.B.H.); and University of British Columbia (G.B.J.M.).
Correspondence to Bertram Pitt, MD, Department of Internal Medicine, Division of Cardiology, University of Michigan Medical Center, 1500 East Medical Center Drive, 3910 Taubman Center, Ann Arbor, MI 48109-0366.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—The results of angiographic studies have suggested that calcium channel–blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both.
Methods and Results—The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively (P=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0.0126-mm decrease in the amlodipine group (P=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization.
Conclusions—Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.
Key Words: amlodipine • atherosclerosis • angiography • ultrasonics • trials • angina • revascularization
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Angiographic studies suggest that calcium channel–blocking agents prevent new coronary artery lesion formation, the progression of minimal coronary lesions, or both.1 2 This could be important in view of data that suggest acute coronary events are often due to plaque rupture of minimal lesions rather than to the progression of advanced lesions.3 4 5 These findings were, however, based on retrospective analyses and should be viewed as hypothesis generating.
Amlodipine besylate (Norvasc) is a long-acting dihydropyridine calcium channel–blocking agent that is lipophilic, has antioxidant effects, and prevents experimental atherosclerosis.6 We postulated that amlodipine would alter the progression of coronary and carotid artery atherosclerosis and therefore reduce the risk of events without the major adverse clinical effects found in previous studies of dihydropyridine calcium channel–blocking agents.1 2 7 8 This report describes the results of the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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General Design Features
The design features have been previously reported6 and are summarized here. PREVENT was a multicenter, randomized, placebo-controlled, double-masked clinical trial of 825 patients who had angiographic evidence of coronary artery disease. The objectives were to evaluate the effect of amlodipine in slowing the 3-year progression of early coronary atherosclerotic lesions as well as the progression of intimal-medial thickness (IMT) in the carotid arteries of a subset of 377 patients. Men and women (30 to 80 years old) were randomized if there was angiographic evidence of 1 focal coronary lesion of
30% diameter stenosis
(nonintervened and noninfarcted) and the presence of 1 lesion with a
5% to 20% stenosis (judged qualitatively) that was not in a
vessel with a 60% lesion. Other eligibility criteria included
diastolic blood pressure of <95 mm Hg, total
cholesterol of <325 mg/dL, and fasting blood glucose of
<200 mg/dL. Randomization was stratified according to clinical center
and history of PTCA. Study medication was initiated at 5 mg QD and increased to 10 mg QD after 2 weeks if tolerated. The final study angiogram was scheduled 36 months after randomization, 7 to 10 days after the study medication was stopped. If a patient had a cardiac procedure performed during follow-up, an "interim" angiogram obtained before the procedure could serve as the final film if a 36-month film could not be obtained and if the interim film occurred no earlier than 35 months after randomization.
Angiographic Methods and Outcomes
The primary objective was to determine whether amlodipine would
reduce the progression of early atherosclerotic segments as measured on
the basis of a change in mean minimal diameter with quantitative
coronary angiography (QCA).9 10 Atherosclerotic
segments were defined as coronary segments with a diameter
stenosis of 
30% at baseline. Up to 12 coronary
segments were used in the analysis of disease
progression.6 Vessels that underwent a procedure at or
before baseline were excluded from the analyses. The baseline
and follow-up films were centrally read pairwise by a certified reader
who was blinded to treatment assignment and the temporal sequencing of
films.
Ultrasonographic Methods and Outcomes
A secondary hypothesis tested whether amlodipine reduced the
progression of atherosclerosis in the carotid arteries
as assessed with B-mode ultrasonography. Progression was based on the
mean of the 3-year regression slopes of the maximum IMT measurements
estimated in each of the 12 separate wall segments (near and far walls
of the common carotid, bifurcation, and internal carotid arteries, on
the right and left sides of the neck).11 This outcome
required fewer participants (377) than the angiographic outcome (825).
There were 2 ultrasound examinations at baseline and 1 every 6 months
thereafter for 36 months. Certified readers who were blinded to
treatment assignment centrally read videotapes.
Monitoring for Clinical Events and Adverse Experiences
The prespecified clinical events were all-cause mortality and
the occurrence of major fatal/nonfatal vascular events or procedures.
Death, myocardial infarction, stroke, hospitalized heart failure, and
hospitalized episodes of unstable angina were classified by an external
events classification committee blinded to treatment assignment with
the use of definitions that were used in other
studies.12 13 14 Confirmation of unstable angina required
hospitalization for typical chest pain and either evidence of
myocardial ischemia (ECG or stress test evidence, or new
angiographic findings of disease) or an indication that this pain was
similar to that of previously documented evidence of ischemia.
The PREVENT adverse experience database was retrospectively reviewed
for terms that suggest cancer or bleeding. All suspected cancers were
classified by an external oncology committee. The a priori
definition for an incident cancer was a new pathologically confirmed
cancer diagnosed at least 1 year postrandomization.
Statistical Analyses
Analysis of the primary end point was performed with a
mixed-effects ANCOVA model that accounted for correlation among
segments measured within patients.15 Treatment effects are
presented in terms of the mean difference and 95% CIs in
3-year change for both minimum diameter and percent diameter
stenosis. In addition to treatment group assignment, the
mixed-effects model included effects that represent segments,
clinical centers, PTCA status at baseline, and random effects for
participants. Secondary analyses of 3-year change in minimal
diameter and percent diameter stenosis were performed within
predefined subgroups after stratification of segments by baseline
stenosis of 0%, >0% to 30%, >30% to 50%, >50%, and
all segments. For analysis of all segments, baseline
stenosis was included as a covariate. Correlation among
segments was accounted for by fitting models to allow different
variances for each segment and a common covariance between
segments (heterogeneous compound symmetry). Segments having
undergone revascularization during follow-up were
excluded from analyses of 36-month angiograms.
The progression of atherosclerosis in the carotid arteries was measured on the basis of the slope of the maximum IMT measurements averaged over 12 separate wall segments as a function of time.11 For this analysis, a mixed-effects model was fit to the maximum IMT measured within each segment at each follow-up. In addition to including random intercepts and slopes for participants, this model contained fixed effects for clinic, treatment, segment, time, and a timextreatment interaction. Treatment effects are presented in terms of the mean difference and 95% CIs on the mean difference in 36-month change in maximal IMT. Analyses of time until the occurrence of clinical outcomes were carried out by log-rank statistics and proportional hazards models to adjust for covariates.16 For clinical outcomes, treatment effects are presented in terms of hazard ratios (HRs) and associated 95% CIs. Simple tests of proportions and means were conducted to evaluate treatment group differences in baseline characteristics. HRs and associated 95% CIs were used to estimate treatment group differences in the 36-month occurrence of adverse events, including cancer and bleeding episodes.
To protect against the increased probability of a type I error, tests of statistical significance were performed at the 0.05 level for the primary angiographic outcome and the overall ultrasound analysis. Because the 5 clinical event outcomes were selected at least in part to address safety concerns,1 2 14 hypothesis tests were interpreted at the 0.05 level so potentially important differences would not be overlooked. In contrast, 95% CIs of treatment effects were calculated for all other secondary outcomes.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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There was good treatment group comparability of baseline characteristics (Table 1
).
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Angiographic Results
Evaluable follow-up angiograms were obtained from 82% (678 of
825) of the participants. There was no evidence that any baseline
characteristic was distributed differentially between treatment groups.
For the primary outcome measure (mean 3-year change in the minimum
diameter in segments of 30% stenosis), the placebo and
amlodipine groups had nearly identical average reductions in the
minimal diameter: 0.084 versus 0.095 mm, respectively
(P=0.38, Table 2).
Amlodipine also failed to show any significant effect for each of the
other angiographic outcomes.
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Ultrasonographic Results
In contrast, amlodipine had a significant effect on the
progression of carotid atherosclerosis (Table 3): the placebo participants had a
0.033-mm increase in IMT during 3-years of follow-up, and the
amlodipine participants had a 0.013-mm decrease (P=0.007).
When stratified according to carotid segment, the estimated 3-year
changes in the common carotid were -0.046-mm regression for amlodipine
versus +0.011-mm progression for placebo (95% CI on difference -0.090
to -0.024 mm).
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Clinical Event Results
Table 4 presents the rates and
Figure 1 presents the life-table
curves for the major clinical events by treatment group. Vital status
was unknown for 2 placebo and 4 amlodipine patients. Amlodipine had no
effect on all-cause mortality. When fatal and nonfatal coronary
and cerebrovascular events are combined, there were 23 amlodipine and
28 placebo participants who experienced an event (HR 0.82 [95% CI
0.47 to 1.42]). Amlodipine reduced the occurrence of the combination
of hospitalized nonfatal congestive heart failure and unstable angina
(61 amlodipine versus 88 placebo, HR 0.65 [0.47 to 0.91]), a
difference primarily due to a reduction in the rate of unstable angina
(60 versus 85, HR 0.67 [0.48 to 0.93]). Amlodipine also reduced
coronary revascularizations (53 versus 86,
HR 0.57 [0.41 to 0.81]) regardless of the use of ß-blocker,
nitrates, or lipid-lowering therapy. When the major and other events
and procedures were combined, there were fewer events in the amlodipine
group (86 versus 116, HR 0.69 [0.52 to 0.92]), mostly attributable to
a difference in unstable angina and
revascularization.
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Table 5 presents adverse experiences
for which there was a treatment group difference with a nominal
P value of 0.10. Twenty-three confirmed incident cancers
were reported during the second and third years of follow-up: 15
amlodipine and 8 placebo (HR 2.13 [0.90 to 5.21]). In the first year
postrandomization, there were 7 and 4 cancers, respectively. This
treatment difference is consistent with reports from
observational studies that link calcium channel blockers to an
increased risk of cancer during the long term, although other studies
have not reported an association.7 There were 10
participants who were hospitalized for bleeding: 5 in each group. All
were on their study medications within 3 days of the hospitalization,
none were on an open-labeled calcium channel blocker, and 1 amlodipine
patient was on warfarin. During follow-up, 40 amlodipine and 28 placebo
participants reported at least 1 bleeding episode, mostly nosebleeds
(HR 1.42 [0.88 to 2.30]), similar to the bleeding risk reported from
larger observational studies.8
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Other Follow-Up Results
Pill count compliance was 79% for amlodipine versus 83% for
placebo. After 4 months of treatment, both systolic and
diastolic blood pressures were lower in the amlodipine
group compared with the placebo group (122/75 versus 130/79
mm Hg, respectively). Although the use of calcium channel blockers and
ACE inhibitors was discouraged during follow-up, 91
amlodipine and 120 placebo patients were receiving a nonstudy calcium
channel blocker for at least some portion of follow-up, and 32
amlodipine and 67 placebo group participants were receiving an ACE
inhibitor. The use of diuretics was almost equal
between treatment groups during follow-up: 111 amlodipine and 93
placebo. After the Scandinavian Simvastatin Survival Study
(4S) results,17 an effort was made to get appropriate
participants to use lipid-lowering agents. The use of statins increased
from 27% at baseline (Table 1
) to 52% for any use during the
course of follow-up (50% amlodipine versus 54% placebo).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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These results fail to support the hypothesis1 2 that amlodipine altered the development or progression of minimal coronary artery lesions. There also was no effect of amlodipine on the progression of moderate or advanced coronary artery stenoses (Table 2
). In contrast, amlodipine had a significant effect on the progression of carotid artery atherosclerosis, as assessed with B-mode ultrasonography. One explanation for this discrepancy may be a difference in the sensitivity of B-mode ultrasonography and coronary angiography for the detection of early arterial disease. Experimental studies show that the growth of atherosclerotic lesions initially affects the vessel wall or external arterial diameter without encroachment on the lumen.18 Another explanation is that the blood pressure–lowering action of amlodipine: reduction in wall stress may have different effects on the carotid and coronary circulation. Regardless, the extent of carotid atherosclerosis as measured by B-mode ultrasonography is associated with increased risk of cardiac mortality and morbidity.19 20 21
Amlodipine had no effect on the risk of all-cause mortality or major cardiovascular events (myocardial infarctions and strokes). However, the statistical power for the detection of a treatment difference in mortality and major morbidity rates was low because of the relatively low incidence rates (eg, <2%/y for myocardial infarction or death).
Of possible importance is the finding that amlodipine significantly reduced the rates of unstable angina and coronary revascularization. An improvement in coronary vasomotor tone could be due to a direct effect on vascular smooth muscle or endothelial function. These reductions in hospitalization for angina pectoris and revascularization were seen in patients on a ß-blocker, nitrate, or lipid-lowering agent. A reduction in the incidence of unstable angina pectoris could result in lower rates of coronary angiography and revascularization. These beneficial effects were not seen in previous angiographic trials with nifedipine or nicardipine in patients with stable coronary artery disease, even though these agents have proved antianginal effects, suggesting that amlodipine may have additional effects.
Of additional importance is the finding that the event curves for
unstable angina pectoris and coronary
revascularizations diverge early. Although lipid
lowering with statins and ACE inhibition with ramipril have reduced
total mortality rates, nonfatal myocardial infarction, and
revascularizations in patients with stable
coronary artery disease,17 22 23 24 there is a lag
of 
1 year before the event curves for these strategies diverge. The
addition of amlodipine could produce an early benefit and further
reduce revascularization and hospitalization for
unstable angina. It may be hypothesized that this would allow statins
or ACE inhibitors a chance to reduce "hard"
ischemic events by altering the underlying pathophysiology of
atherosclerosis, plaque rupture, or thrombosis and
thereby possibly avoid coronary
revascularization. Thus, amlodipine might further
reduce the need for coronary
revascularizations observed in previous randomized
trials of medical therapy versus coronary angioplasty, such as
Randomised Intervention Treatment of Angina (RITA-2) and Atorvastatin
Versus Revascularization Treatment
(AVERT).25 26 This strategy, however, requires prospective
testing.
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Acknowledgments |
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This clinical trial was supported by a grant from Pfizer, Inc to Wake Forest University School of Medicine, Winston-Salem, NC.
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Footnotes |
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1 A list of all PREVENT study investigators and institutions is given in the Appendix.
Drs Pitt, Byington, and Miller serve as consultants to Pfizer; Dr Hunninghake currently works on various other research projects supported by Pfizer and serves on the Pfizer Speakers Bureau; and Dr Mancini serves as a consultant to both Merck and Parke-Davis.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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PREVENT Participating Investigators and Institutions
Clinical Centers
David C. Booth, MD (University of Kentucky Medical Center), Anthony Chapekis, MD (Midwest Cardiology); Vivian Clark, MD (Henry Ford Hospital); Gilles Côté, MD (Montreal Heart Institute); Robert Feldman, MD (Mediquest Research Group); David Herrington, MD, MHS (Wake Forest University School of Medicine); Lyall A.J. Higginson, MD (University of Ottawa Heart Institute); Craig Hjemdahl-Monsen, MD (New York Medical College); Donald B. Hunninghake, MD (University of Minnesota Hospital/Clinic); Glen J. Kowalchuk, MD (Carolinas Medical Center); Stephen Mallon, MD (University of Miami School of Medicine); Michael Miller, MD (University of Maryland Hospital); K.B. Ramanathan, MD (University of Tennessee); Donald Ricci, MD (Vancouver Hospital/Health Sciences Center); David Waters, MD (Hartford Hospital); Steven W. Werns, MD (University of Michigan Medical Center).
Steering Committee Cochairmen
Curt D. Furberg, MD, PhD (Wake Forest University School of
Medicine); Bertram Pitt, MD (University of Michigan Medical
Center).
Angiography Reading Center
G.B. John Mancini, MD (University of British Columbia).
Ultrasound Reading Center
Ward Riley, PhD (Wake Forest University School of Medicine).
Data Coordinating Center
Robert P. Byington, PhD, Michael E. Miller, PhD (Wake Forest
University School of Medicine).
Central Laboratory
Smithkline Beecham Clinical Laboratories.
Sponsor
Pfizer, Inc/US Pharmaceuticals Group: Robert Scott, MD, Ethel
Buebendorf, RN.
Received January 11, 2000; revision received April 26, 2000; accepted May 2, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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 P. Valensi, J.-P. Baguet, R. Asmar, S. Nisse-Durgeat, and J.-M. Mallion Effect of candesartan cilexetil on carotid intima-media thickness in hypertensive type 2 diabetic patients. MITEC study: design and baseline characteristics The British Journal of Diabetes & Vascular Disease, January 1, 2007; 7(1): 18 - 24. [Abstract] [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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 P. Raggi, A. Taylor, Z. Fayad, D. O'Leary, S. Nissen, D. Rader, and L. J. Shaw Atherosclerotic Plaque Imaging: Contemporary Role in Preventive Cardiology Arch Intern Med, November 14, 2005; 165(20): 2345 - 2353. [Abstract] [Full Text] [PDF]
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P.-J. Touboul, J. Labreuche, E. Vicaut, P. Amarenco, and on behalf of the GENIC Investigators Carotid Intima-Media Thickness, Plaques, and Framingham Risk Score as Independent Determinants of Stroke Risk Stroke, August 1, 2005; 36(8): 1741 - 1745. [Abstract] [Full Text] [PDF]
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Blood Pressure Lowering Treatment Trialists' Colla Effects of Different Blood Pressure-Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes Mellitus: Results of Prospectively Designed Overviews of Randomized Trials Arch Intern Med, June 27, 2005; 165(12): 1410 - 1419. [Abstract] [Full Text] [PDF]
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E. Shinoda, Y. Yui, K. Kodama, A. Hirayama, H. Nonogi, K. Haze, T. Sumiyoshi, S. Hosoda, C. Kawai, and for the Japan Multicenter Investigation for Cardio Quantitative Coronary Angiogram Analysis: Nifedipine Retard Versus Angiotensin-Converting Enzyme Inhibitors (JMIC-B Side Arm Study) Hypertension, June 1, 2005; 45(6): 1153 - 1158. [Abstract] [Full Text] [PDF]
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 M. B. Kahn, K. Boesze-Battaglia, D. W. Stepp, A. Petrov, Y. Huang, R. P. Mason, and T. N. Tulenko Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H591 - H600. [Abstract] [Full Text] [PDF]
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 J C Spratt and E Camenzind Plaque stabilisation by systemic and local drug administration Heart, December 1, 2004; 90(12): 1392 - 1394. [Full Text] [PDF]
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M. F. Walter, R. F. Jacob, B. Jeffers, M. M. Ghadanfar, G. M. Preston, J. Buch, and R. P. Mason Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: A longitudinal analysis of the PREVENT study J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1996 - 2002. [Abstract] [Full Text] [PDF]
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S. E. Nissen, E. M. Tuzcu, P. Libby, P. D. Thompson, M. Ghali, D. Garza, L. Berman, H. Shi, E. Buebendorf, E. J. Topol, et al. Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure: The CAMELOT Study: A Randomized Controlled Trial JAMA, November 10, 2004; 292(18): 2217 - 2225. [Abstract] [Full Text] [PDF]
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 G. B. J. Mancini, B. Dahlof, and J. Diez Surrogate Markers for Cardiovascular Disease: Structural Markers Circulation, June 29, 2004; 109(25_suppl_1): IV-22 - IV-30. [Full Text] [PDF]
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K.-i. Aihara, H. Azuma, N. Takamori, Y. Kanagawa, M. Akaike, M. Fujimura, T. Yoshida, S. Hashizume, M. Kato, H. Yamaguchi, et al. Heparin Cofactor II Is a Novel Protective Factor Against Carotid Atherosclerosis in Elderly Individuals Circulation, June 8, 2004; 109(22): 2761 - 2765. [Abstract] [Full Text] [PDF]
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C. M.M. Lawes, D. A. Bennett, V. L. Feigin, and A. Rodgers Blood Pressure and Stroke: An Overview of Published Reviews Stroke, April 1, 2004; 35(4): 1024 - 1033. [Abstract] [Full Text] [PDF]
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R. Candido, T. J. Allen, M. Lassila, Z. Cao, V. Thallas, M. E. Cooper, and K. A. Jandeleit-Dahm Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis Circulation, March 30, 2004; 109(12): 1536 - 1542. [Abstract] [Full Text] [PDF]
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C. M.M. Lawes, D. A. Bennett, V. L. Feigin, and A. Rodgers Blood Pressure and Stroke: An Overview of Published Reviews Stroke, March 1, 2004; 35(3): 776 - 785. [Abstract] [Full Text] [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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C. Kataoka, K. Egashira, M. Ishibashi, S. Inoue, W. Ni, K.-i. Hiasa, S. Kitamoto, M. Usui, and A. Takeshita Novel anti-inflammatory actions of amlodipine in a rat model of arteriosclerosis induced by long-term inhibition of nitric oxide synthesis Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H768 - H774. [Abstract] [Full Text] [PDF]
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 R.P. Mason, P. Marche, and T.H. Hintze Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists: Ancillary Actions of Amlodipine Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2155 - 2163. [Abstract] [Full Text] [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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R. Tabrizchi Amlodipine and endothelial nitric oxide synthase activity Cardiovasc Res, October 1, 2003; 59(4): 807 - 809. [Full Text] [PDF]
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H. Lenasi, K. Kohlstedt, B. Fichtlscherer, A. Mulsch, R. Busse, and I. Fleming Amlodipine activates the endothelial nitric oxide synthase by altering phosphorylation on Ser1177 and Thr495 Cardiovasc Res, October 1, 2003; 59(4): 844 - 853. [Abstract] [Full Text] [PDF]
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T. Yu, I. Morita, K. Shimokado, T. Iwai, and M. Yoshida Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction Hypertension, September 1, 2003; 42(3): 329 - 334. [Abstract] [Full Text] [PDF]
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J A Dens, W J Desmet, P Coussement, I K De Scheerder, K Kostopoulos, P Kerdsinchai, C Supanantaroek, and J H Piessens Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study Heart, August 1, 2003; 89(8): 887 - 892. [Abstract] [Full Text] [PDF]
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R. P. Mason and R. F. Jacob Membrane Microdomains and Vascular Biology: Emerging Role in Atherogenesis Circulation, May 6, 2003; 107(17): 2270 - 2273. [Full Text] [PDF]
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J. A Staessen, J.-G. Wang, and W. H Birkenhager Outcome beyond blood pressure control? Eur. Heart J., March 2, 2003; 24(6): 504 - 514. [Full Text] [PDF]
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V. S. Monroe, R. A. Kerensky, E. Rivera, K. M. Smith, and C. J. Pepine Pharmacologic plaque passivation for the reduction of recurrent cardiac events in acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 23S - 30S. [Abstract] [Full Text] [PDF]
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The ENCORE Investigators* Effect of Nifedipine and Cerivastatin on Coronary Endothelial Function in Patients With Coronary Artery Disease: The ENCORE I Study (Evaluation of Nifedipine and Cerivastatin On Recovery of coronary Endothelial function) Circulation, January 28, 2003; 107(3): 422 - 428. [Abstract] [Full Text] [PDF]
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F. H. Messerli, W. B. White, and J. A. Staessen If only cardiologists did properly measure blood pressure: Blood pressure recordings in daily practice and clinical trials J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2201 - 2203. [Abstract] [Full Text] [PDF]
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M. R. Law, H. C. Watt, and N. J. Wald The Underlying Risk of Death After Myocardial Infarction in the Absence of Treatment Arch Intern Med, November 25, 2002; 162(21): 2405 - 2410. [Abstract] [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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 S. H. Hong, W. Riley, J. Rhyne, G. Friel, and M. Miller Lack of Association between Increased Carotid Intima-Media Thickening and Decreased HDL-Cholesterol in a Family with a Novel ABCA1 Variant, G2265T Clin. Chem., November 1, 2002; 48(11): 2066 - 2070. [Abstract] [Full Text] [PDF]
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 J.-G. Wang and J. A. Staessen Conventional Therapy and Newer Drug Classes for Cardiovascular Protection in Hypertension J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S208 - 215. [Abstract] [Full Text]
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R. Nosadini and G. Tonolo Cardiovascular and Renal Protection in Type 2 Diabetes Mellitus: The Role of Calcium Channel Blockers J. Am. Soc. Nephrol., November 1, 2002; 13(90003): S216 - 223. [Abstract] [Full Text]
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R. P. Byington, C. D. Furberg, D. M. Herrington, J. A. Herd, D. Hunninghake, M. Lowery, W. Riley, T. Craven, L. Chaput, C. C. Ireland, et al. Effect of Estrogen Plus Progestin on Progression of Carotid Atherosclerosis in Postmenopausal Women With Heart Disease: HERS B-Mode Substudy Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1692 - 1697. [Abstract] [Full Text] [PDF]
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J. E. Deanfield, J.-M. Detry, P. Sellier, P. R. Lichtlen, E. Thaulow, J. Bultas, C. Brennan, S. T. Young, B. Beckerman, and CAPE II Trial Investigators Medical treatment of myocardial ischemia in coronary artery disease: effect of drug regime and irregular dosing in the CAPE II trial J. Am. Coll. Cardiol., September 4, 2002; 40(5): 917 - 925. [Abstract] [Full Text] [PDF]
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S. Achenbach, D. Ropers, K. Pohle, A. Leber, C. Thilo, A. Knez, T. Menendez, R. Maeffert, M. Kusus, M. Regenfus, et al. Influence of Lipid-Lowering Therapy on the Progression of Coronary Artery Calcification: A Prospective Evaluation Circulation, August 27, 2002; 106(9): 1077 - 1082. [Abstract] [Full Text] [PDF]
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L. A. Lange, D. W. Bowden, C. D. Langefeld, L. E. Wagenknecht, J. J. Carr, S. S. Rich, W. A. Riley, and B. I. Freedman Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes Stroke, July 1, 2002; 33(7): 1876 - 1881. [Abstract] [Full Text] [PDF]
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W.A. Riley Carotid intima-media thickness: risk assessment and scanning protocol Eur. Heart J., June 2, 2002; 23(12): 916 - 918. [Full Text] [PDF]
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W. Klein Treatment patterns in stable angina: objectives and reality Eur. Heart J. Suppl., November 1, 2001; 3(suppl_O): O8 - O11. [Abstract] [PDF]
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F. H. Messerli, B. Pitt, R. P. Byington, C. D. Furberg, D. B. Hunninghake, G.B. J. Mancini, M. E. Miller, and W. Riley Confusing Press Releases and the PREVENT Study Response Circulation, October 30, 2001; 104 (18): e95 - e95. [Full Text] [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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M. R. Goldstein, B. Pitt, R. P. Byington, C. D. Furberg, M. E. Miller, W. Riley, D. B. Hunninghake, and G.B. J. Mancini Does Amlodipine Increase Cancer Incidence? Circulation, July 10, 2001; 104 (2): e5 - e5. [Full Text] [PDF]
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J. R. Kizer and S. E. Kimmel Epidemiologic Review of the Calcium Channel Blocker Drugs: An Up-to-date Perspective on the Proposed Hazards Arch Intern Med, May 14, 2001; 161(9): 1145 - 1158. [Abstract] [Full Text] [PDF]
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E. M. Lonn, S. Yusuf, V. Dzavik, C. I. Doris, Q. Yi, S. Smith, A. Moore-Cox, J. Bosch, W. A. Riley, and K. K. Teo Effects of Ramipril and Vitamin E on Atherosclerosis : The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) Circulation, February 20, 2001; 103(7): 919 - 925. [Abstract] [Full Text] [PDF]
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L. H. Opie First line drugs in chronic stable effort angina--the case for newer, longer-acting calcium channel blocking agents J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1967 - 1971. [Abstract] [Full Text] [PDF]
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