This Article Abstract Full Text (PDF) All Versions of this Article: 35/12/2807    most recent 01.STR.0000147041.00840.59v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zanchetti, A. Search for Related Content PubMed PubMed Citation Articles by Zanchetti, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cholesterol High Blood Pressure Hazardous Substances DB HYDROCHLOROTHIAZIDE Related Collections Clinical Studies Lipids Cardiovascular Pharmacology Imaging Doppler ultrasound, Transcranial Doppler etc.

(Stroke. 2004;35:2807.)
© 2004 American Heart Association, Inc.

Original Contributions

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

Alberto Zanchetti, MD; Gaetano Crepaldi, MD; M. Gene Bond, PhD; Giuseppe Gallus, MD; Fabrizio Veglia, PhD; Giuseppe Mancia, MD; Alessandro Ventura, MD; Giovannella Baggio, MD; Lorena Sampieri, MD; Paolo Rubba, MD; Giovanni Sperti, MD Alberto Magni, MD on behalf of PHYLLIS Investigators

From the Istituto Auxologico Italiano, Ospedale Maggiore, University of Milan, Italy (A.Z., L.S.); the Clinica Medica I, University of Padova, Italy (G.C.); Wake Forest University School of Medicine, Winston-Salem, NC (M.G.B.); the Department of Biometrics and Clinical Statistics, University of Milan, Italy (G.G.); the Centro Cardiologico Monzino, Italy (F.V.); the Clinica Medica, University of Milano-Bicocca, Italy (G.M.); the Clinica Medica, University of Perugia, Italy (A.V.); Ospedale Civile, Padova, Italy (G.B.); the University Federico II, Napoli, Italy (P.R.); Bristol-Myers Squibb, Rome, Italy (G.S.); and Menarini, Florence, Italy (A.M.).

Correspondence to Prof Alberto Zanchetti, Centro di Fisiologia Clinica e Ipertensione, Via F. Sforza, 35 20122 Milano, Italy. E-mail alberto.zanchetti{at}unimi.it

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background and Purpose— The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies.

Methods— A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBM_max).

Results— CBM_max significantly progressed (0.010±0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBM_max changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. "Clinic" and "ambulatory" blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by 1 mmol/L in groups C and D.

Conclusions— Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide.

Key Words: arteriosclerosis • carotid arteries • hypertension • lipids

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
Ultrasound measurement of carotid intima-media thickness (IMT) is used to measure asymptomatic atherosclerosis progression. Studies in hypertensive patients showed a significant slowing down with calcium antagonists compared with diuretics^1,2 or ß-blockers.³ Two trials^4,5 explored the effects of angiotensin-converting enzyme (ACE) inhibitors versus placebo, with contradictory results. A number of studies tested the effects of lipid lowering by statins on carotid IMT,^6–12 showing significant retardation of IMT progression, but none was conducted in hypertensives.

The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) aimed to test in hypertensive patients with hypercholesterolemia and asymptomatic atherosclerosis whether (1) antihypertensive therapy with the ACE inhibitor fosinopril was more effective on carotid atherosclerosis progression than antihypertensive therapy with hydrochlorothiazide; (2) lipid lowering with pravastatin was more effective than placebo when associated with either hydrochlorothiazide or fosinopril; and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies on carotid atherosclerosis.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
Participants and Interventions
In 13 Italian hospitals, men and postmenopausal women aged 45 to 70 years with untreated or uncontrolled hypertension, hypercholesterolemia, asymptomatic carotid atherosclerosis (maximum carotid IMT, T_max, 1.3 to 4.0 mm), no previous cardiovascular events, and giving informed consent underwent 6-week washout under triple placebo and American Heart Association low-lipid diet. At washout end, those maintaining systolic blood pressure (SBP) 150 to 210 mm Hg, diastolic blood pressure (DBP) 95 to 115 mm Hg, serum low-density lipoprotein (LDL) cholesterol 4.14 to 5.17 mmol/L (160 to 200 mg/dL), and triglycerides 3.39 mmol/L (300 mg/dL) were randomized to: (A) hydrochlorothiazide, 25 mg QD plus fosinopril placebo and pravastatin placebo; (B) fosinopril, 20 mg QD plus hydrochlorothiazide placebo and pravastatin placebo; (C) hydrochlorothiazide, 25 mg QD, and pravastatin, 40 mg QD plus fosinopril placebo; (D) fosinopril, 20 mg QD, and pravastatin, 40 mg QD plus hydrochlorothiazide placebo. Randomization was computer generated with a block size of 4. If DBP was not <90 mm Hg or <95 mm Hg with a fall of 10 mm Hg, open-label nifedipine gastrointestinal therapeutic system (GITS), 30 mg QD, was added after 3 months to be eventually increased to 60 mg after 6 months. Low-lipid diet was maintained throughout the study. Patients and study personnel were blinded to treatment assignment. The protocol was approved by ethics committees of all institutions involved.

Measurements
Certified sonographers at 13 participating units performed duplicate B-mode carotid scans at randomization and subsequently at yearly intervals during 3 years by a Biosound 2000IISA (Biosound) with an 8-MHz annular array transducer. All scans were read at the Ultrasound Coordinating Center. Three mercury manometer measurements of sitting clinic blood pressure were taken at baseline and every 3 months thereafter. Ambulatory blood pressure monitoring was done at baseline, yearly intervals, and study end, and read centrally. Blood chemistry was performed at baseline and every 6 months in certified laboratories. All data were handled by an independent statistical analysis center.

Outcomes
Primary outcome was rate of change in mean maximum IMT of the 8 far and near walls in distal common carotids and bifurcations bilaterally (CBM_max). Duplicate scans were read blindly during study. Readers’ drift was checked from rereading single scans of 4 far walls at study end, with time sequence randomized. Differences between old and new readings were estimated by linear regression against treatment time and original values corrected by subtracting fitted values at corresponding dates from original values. Slopes were calculated from a mean (SD) of 3.6 (0.6) time points in duplicate and from a mean (SD) of 7.73 (0.72) walls. Secondary outcomes were: (1) changes in mean maximum IMT of the 4 far and near walls in distal common carotids (CC-IMT) and separately in carotid bifurcations (Bif-IMT); (2) changes in clinic and ambulatory blood pressure; and (3) changes in serum total, LDL, and high-density lipoprotein (HDL) cholesterol and other laboratory variables.

Statistics
A sample size of 500 (125 for treatment group) with a 20% dropout rate was calculated to provide 2-sided 5% significance and 80% power to detect a mean (±SD) difference in CBM_max changes of 0.0150 (±0.0373) mm per year (assumption derived from Verapamil in Hypertension and Atherosclerosis Study [VHAS]¹ and Carotid Atherosclerosis Italian Ultrasound Study [CAIUS]¹⁰).

Treatment-related IMT changes were calculated as means±SE and 95% CIs of yearly progressions (slopes), and of differences between final and baseline scans and significance tested by ANOVA. The analysis plan specified pairwise comparisons of groups B, C, and D with group A. Because each pairwise comparison was intended to answer different questions (B versus A, superiority of fosinopril over hydrochlorothiazide in subjects not receiving pravastatin; C versus A, superiority of pravastatin over placebo in subjects receiving hydrochlorothiazide; D versus A, superiority of fosinopril plus pravastatin over hydrochlorothiazide plus placebo), no Bonferroni adjustment of P values was used to control experimental type I error, as suggested by Cook and Farewell.¹³ Differences in IMT changes between each pair of the 4 treatment groups were expressed as means±SE and 95% CI and tested by ANCOVA with treatment and baseline IMT as covariates. No logarithmic transformation of data was found to be necessary. The analysis plan also included a test of interaction to provide indication on possible additive effects of the 2 treatments on the primary outcome.

On-treatment clinic and ambulatory blood pressures and heart rates and metabolic variables were compared with baseline by paired t test, and changes between randomized groups compared by unpaired t test or multiple-measurement ANCOVA. All significance tests were 2-sided.

The present article reports intention-to-treat analyses.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Patients
A total of 950 patients were screened by ultrasound and 508 patients randomly allocated to double-blind treatment (average treatment duration 2.6 years). Baseline characteristics are listed in Table 1. There was no major between-group difference except for smokers (fewer in group D).

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of Patients Randomly Allocated to the 4 Treatment Regimens

Treatment
A total of 79.8% of patients in group A, 80.9% in B, 84.2% in C, and 84.2% in D remained on monotherapy with hydrochlorothiazide or fosinopril until the last study visit. The remainder received additionally open-label nifedipine GITS, 30 to 60 mg daily. A total of 98% of patients in groups C and D remained on pravastatin. No patients in groups A and B were on pravastatin or another lipid-lowering agent.

Treatment-Related Changes in Carotid Wall
The primary variable CBM_max significantly progressed by 0.010±0.004 mm per year (P=0.01), with a final difference from baseline of 0.025±0.011 mm (P=0.03) in group A (hydrochlorothiazide alone). There was no significant progression in the other treatment groups. Slopes of CBM_max changes in groups B (fosinopril alone; –0.002±0.004 mm; NS), C (hydrochlorothiazide+pravastatin; –0.002±0.004 mm; NS), and D (fosinopril+pravastatin; –0.002±0.004 mm; NS) were all significantly different (P=0.02 to 0.03) from slope in group A (hydrochlorothiazide alone); B versus A –0.012 mm per year, P=0.03; C versus A –0.012 mm per year, P=0.03; D versus A –0.012 mm per year, P=0.02), but not between themselves (Figure 1). Identical differences between treatment groups with identical levels of significance were found when using original measurements uncorrected by final controls for possible drift. Considering CBM_max differences between final and baseline scans (Figure 1), the same trends were observed, although only the difference between groups D and A formally achieved statistical significance (P=0.04). As indicated by the interaction test (P=0.08), the assumption of additive effects appeared unlikely; indeed, the effect of fosinopril plus pravastatin on CBM_max slope was identical to that of fosinopril alone.

View larger version (20K): [in this window] [in a new window]   Figure 1. Changes in CBMmax slopes (top left) and between final and baseline measurements (top right) in the 4 treatment groups (top). Means±95% CIs. The bottom shows estimated treatment effects as means (circles) with 95% CIs (horizontal lines) for slopes and final minus baseline measurements (F–B). HCTZ indicates hydrochlorothiazide; FOS, fosinopril; Plac, placebo; Prava, pravastatin. *P<0.05; P<0.01.

Changes in yearly progression (Figure 2, left) or final difference from baseline in CC-IMT were small and nonsignificant in group A, and no significant progression in CC-IMT occurred in any of the other groups. However, a marked and significant yearly progression in Bif-IMT was found in group A with no significant progression in the other groups (Figure 2, right). Significant differences in yearly Bif-IMT progression were seen by comparing groups B (–0.023 mm per year; P=0.012), C (–0.019 mm per year; P=0.037), or D (–0.22 mm per year; P=0.007) with group A.

View larger version (21K): [in this window] [in a new window]   Figure 2. Yearly changes in CC-IMT (top left) and Bif-IMT (top right) in the 4 treatment groups. Means ±95% CIs. Bottom, Estimated treatment effects. Symbols and abbreviations as in Figure 1.

Carotid internal diameter changed very slightly and nonsignificantly in the 4 groups, and Spearman correlation coefficients with CBM_max changes were extremely small (A –0.0404; B 0.0117; C 0.0942; D 0.0091) and statistically nonsignificant. Consequently, adjustments of CBM_max progressions using diameter changes as covariate influenced results in an irrelevant way.

Treatment-Related Changes in Blood Pressure, Heart Rate, and Metabolic Variables
Clinic SBP, DBP, and pulse pressure (PP) decreased markedly and significantly (P<0.001) in all groups, with no significant between-group differences. Changes in ambulatory SBP, DBP, and PP were smaller but all significant versus baseline (SBP and DBP, P<0.001; PP P<0.05) and nonsignificantly different between groups (Figure 3). Heart rate did not significantly change in any group.

View larger version (25K): [in this window] [in a new window]   Figure 3. Clinic and 24-hour ambulatory (24h Amb) blood pressure changes in the treatment groups. Means of all values after 3 months to study end±SEM. All other abbreviations as in Figure 1.

Metabolic changes (Table 2) consisted in marked and highly significant reductions in total and LDL cholesterol in the groups receiving pravastatin, but a significant although smaller decrease also occurred in group B. HDL cholesterol significantly increased in group D, and triglycerides in group A. Serum urate significantly increased and serum potassium significantly decreased in groups receiving hydrochlorothiazide.

View this table: [in this window] [in a new window]   TABLE 2. Metablic Changes During Randomized Treatment

Safety
There were too few cardiovascular events among PHYLLIS patients to allow statistical evaluation: 4 myocardial infarctions (3 in A, 1 in D), 1 stroke (D), 1 cardiovascular death (D), and 2 cases of cancer (1 each in B and C). Patients with creatine-phosphokinase increases to >600 U/L were 1, 5, 5, and 2 in each group.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
PHYLLIS conclusions rest on careful recording of duplicate carotid scans by trained sonographers using the same high-precision instruments and probes, with centralized reading, study personnel blinded to treatment, and correction for possible drift or bias. Fosinopril and pravastatin exerted their effects predominantly or exclusively at the bifurcation, a preferred location for the hemodynamic effects of hypertension and for atherosclerosis, and this strongly supports the conclusion that fosinopril and pravastatin blunt progression of carotid atherosclerosis.

PHYLLIS shows ACE inhibitors may exert an antiatherosclerotic action, a matter until now undecided, confirming for fosinopril versus hydrochlorothiazide the finding of the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E (SECURE)⁴ for ramipril versus placebo, and explaining the negative results of PART-2,⁵ because this study only investigated common carotid IMT, which was uninfluenced by fosinopril in PHYLLIS. The IMT effect of fosinopril versus hydrochlorothiazide (–0.012 mm per year) had similar order of magnitude as ramipril versus placebo in SECURE⁴ (–0.008 mm per year), calcium antagonists versus diuretics in VHAS¹ (–0.010 mm per year) and INSIGHT² (–0.0081 mm per year), and versus atenolol in European Lacidipine Study on Atherosclerosis (ELSA)³ (–0.006 mm per year).

PHYLLIS also shows that lipid-lowering drugs reduce progression of carotid IMT in hypertensive patients, not only in those with vascular or coronary disease as in previous studies.^6–12 The extent of the CBM_max effect of pravastatin in PHYLLIS (–0.012 mm per year) was of the same magnitude as in previous placebo-controlled studies measuring carotid CBM_max or M_max (–0.009 to –0.019 mm per year)^6–8,10,12 In PHYLLIS, the effect of pravastatin was predominantly found at the bifurcation, as in a previous study,¹⁰ although other studies found an effect on CC-IMT.^7–9,11,12 In PHYLLIS, CC-IMT did not significantly progress under hydrochlorothiazide, and this might have prevented any further pravastatin (as well as fosinopril) action at that level.

Several tentative explanations can be offered for the absence of additive effect of fosinopril plus pravastatin: (1) because either fosinopril or pravastatin fully blocked progression of carotid IMT, no further effect could be seen by using the 2 drugs together; (2) a higher statin dose with greater cholesterol reduction was necessary; (3) additive effects may have required a time span >2.6 years; and (4) associating an ACE inhibitor and a statin may influence composition rather than thickness of carotid wall or plaques.

We can exclude that the greater antiatherogenic action of fosinopril versus hydrochlorothiazide was related to greater BP reduction because clinic and ambulatory values were never reduced to a greater extent by fosinopril. A calcium antagonist with documented action on carotid IMT² was used in a minority of patients and exactly in the same proportion in groups A and B, and in a slightly lower proportion in groups C and D. Animal experiments with various ACE inhibitors¹⁴ have shown efficacy on various models of atherosclerosis and suggested actions on endothelium or other vascular components. The antiatherosclerotic effect of pravastatin in PHYLLIS was not attributable to greater BP reduction but was associated with marked decrease in total and LDL cholesterol, some increase in HDL cholesterol, and possibly, antiproliferative and antinflammatory actions of statins.¹⁵

There were too few events in PHYLLIS patients to be correlated with carotid changes or treatment regimens. Therefore, it cannot be concluded from our observations that the smaller carotid IMT progression occurring with fosinopril (versus hydrochlorothiazide) or pravastatin added to hydrochlorothiazide is necessarily associated with a lower cardiovascular risk. However, the IMT changes observed with fosinopril (versus hydrochlorothiazide) and associating pravastatin with hydrochlorothiazide were of similar magnitude to those induced by lipid-lowering drugs in patients with coronary heart disease accompanied by reduced incidence of cardiovascular events.^6,7 Cholesterol changes were also of the same magnitude as in a recent study in hypertensives in which lipid lowering significantly decreased cardiovascular event incidence.¹⁶

The finding that ACE inhibitors and diuretics have a comparable effect on cardiovascular morbidity and mortality¹⁷ (nonetheless, a nonunanimous finding¹⁸) does not necessarily suggest that differences in carotid atherosclerosis progression described in PHYLLIS between fosinopril and hydrochlorothiazide have no clinical relevance. On the contrary, it may support the opinion of recent European hypertension guidelines¹⁹ that event-based trials may be too short and commonly performed in too complicated hypertensives to detect differences in morbidity/mortality between different active antihypertensive treatments. Trials showing treatment-related differences in organ damage (ie, on alterations that in the history of cardiovascular disease are intermediate in time) may provide useful indications on a longer-term perspective.

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
Principal Investigators
A. Zanchetti, G. Crepaldi, M.G. Bond.

Scientific Committee
E. Ambrosioni, G. Baggio, C. Dal Palù, G.V. Gallus, B. Magnani, G. Mancia, M. Mancini, R. Paoletti, A. Ventura, G.B. Leproux, A. Magni.

Ultrasound Coordinating Center
M.G. Bond.

Ambulatory Blood Pressure Monitoring Coordinating Center
G. Mancia, G. Parati.

Statistical Analysis Center
G.V. Gallus, F. Veglia.

Data Monitoring Unit
M. Ricci, E. Serrotti.

Participating Units
A. Rappelli, P. Dessi-Fulgheri, E. Espinosa, R. Catalini, O. Zingaretti (Ancona); A. Capurso, N. Barile, C. Macchiarulo, A. Venezia (Bari); A. Gaddi, S. Rimondi, L. Finazzo, C. Mussoni (Bologna); E. Agabiti-Rosei, M.L. Muiesan, C. Monteduro, M. Salvetti (Brescia); R. Balestreri, G. Lotti, S. Bertolini, N.R. Musso, C. Barone, O. Franza (Genova); G. Leonetti, L. Sampieri, C. Cuspidi, R. Chianca, M. Bombelli, G. Foglia, S. Pellizzoli, G. Pontiggia (Milano); C. Sirtori, F. Pazzucconi, D. Baldassarre (Milano); F. Pasanisi, A. Iannuzzi, F. Faccenda (Napoli); A. Semplicini, A. Pontebasso, A. Calabro, G. Brisotto (Padova); G. Ciuffetti, M. Politano, G. Brunetti, B. Fiorucci (Perugia); A. Salvetti, A.H. Basen, S. Buralli (Pisa); L. Campanacci, G. Guarnieri, G. Bellini, L. Cattin, M. Fisicaro, M. Tonizzo (Trieste); A. Lechi, M. Muggeo, M. Ribul, D. Travia (Verona).

	Acknowledgments

 
PHYLLIS was an investigator-generated trial sponsored by Bristol-Myers Squibb Italy, Rome, and Menarini, Florence. All authors have received research grants or lecture honoraria from the sponsors.

	Footnotes

 
Dr Sperti is an employee of Bristol-Myers Squibb, and Dr Magni is an employee of Menarini.

Received June 21, 2004; revision received August 24, 2004; accepted September 16, 2004.

	References

Top Abstract Introduction Methods Results Discussion Appendix References

 

1. Zanchetti A, Agabiti-Rosei E, Dal Palù C, Leonetti G, Magnani B, Pessina A. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens. 1998; 16: 1667–1676.[CrossRef][Medline] [Order article via Infotrieve]
2. Simon A, Gariépy J, Moyse D, Levenson J. Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation. 2001; 103: 2949–2954.[Abstract/Free Full Text]
3. Zanchetti A, Bond M G, Hennig M, Neiss A, Mancia G, Dal Palù C, Hansson L, Magnani B, Rahn K-H, Reid JL, Rodicio J, Safar M, Eckes L, Rizzini P. 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. 2002; 106: 2422–2427.[Abstract/Free Full Text]
4. Lonn EM, Yusuf S, Dzavik V, Doris Cl, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley WA, Teo KK. 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. 2001; 103: 919–925.[Abstract/Free Full Text]
5. MacMahon S, Sharpe N, Gamble G, Clague A. Mhurchu C N, Clark T, Hart H, Scott J, White H. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. J Am Coll Cardiol. 2000; 36: 438–443.[Abstract/Free Full Text]
6. Furberg CS, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, Young B. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994; 90: 1679–1687.[Abstract/Free Full Text]
7. Crouse JR III, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD. Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol. 1995; 75: 455–459.[CrossRef][Medline] [Order article via Infotrieve]
8. Salonen R, Nyyssönen K, Porkkala E, Rummukainen J, Belder R, Park J-S, Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerosis progression in carotid and femoral arteries. Circulation. 1995; 92: 1758–1764.[Abstract/Free Full Text]
9. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C, Alaupovic P, Kwong-Fu H, Azen SP. Reduction in carotid arterial wall thickness using lovastatin and dietary therapy. A randomized, controlled clinical trial. Ann Intern Med. 1996; 124: 548–556.[Abstract/Free Full Text]
10. Mercuri M, Bond MG, Sirtori CR, Veglia F, Crepaldi G, Feruglio FS, Deskovic G, Ricci G, Rubba P, Mancini M, Gallus G, Bianchi G, D’Alò G, Ventura A. Pravastatin reduces carotid-intima-media thickness progression in an asymptomatic hypercholesterolemic Mediterranean population: the Carotid Atherosclerosis Italian Ultrasound Study. Am J Med. 1996; 101: 627–634.[CrossRef][Medline] [Order article via Infotrieve]
11. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J White H. Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Results of the LIPID Atherosclerosis Substudy. Circulation. 1998; 97: 1784–1790.[Abstract/Free Full Text]
12. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. 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). Circulation. 2001; 103: 1721–1726.[Abstract/Free Full Text]
13. Cook JR, Farewell VT. Multiplicity considerations in the design and analysis of clinical trials. J R Stat Soc A. 1996; 159: 93–110.[CrossRef]
14. Kowala MC, Recce R, Beyer S, Aberg G. Regression of early atherosclerosis in hyperlipidemic hamsters induced by fosinopril and captopril. J Cardiovasc Pharmacol. 1995; 25: 179–186.[Medline] [Order article via Infotrieve]
15. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98: 839–844.[Abstract/Free Full Text]
16. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen S, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361: 1149–1158.[CrossRef][Medline] [Order article via Infotrieve]
17. Staessen JA, Wang J, Thijs L. Cardiovascular prevention and blood pressure reduction: a qualitative overview updated until 1 March 2003. J Hypertens. 2003; 21: 1055–1076.[CrossRef][Medline] [Order article via Infotrieve]
18. Wing LMH, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GLR, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West M. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003; 348: 583–592.[Abstract/Free Full Text]
19. Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology. Guidelines for the management of arterial hypertension. J Hypertens. 2003; 21: 1011–1053.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				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]

				S. Bonovas and N. M. Sitaras Does pravastatin promote cancer in elderly patients? A meta-analysis Can. Med. Assoc. J., February 27, 2007; 176(5): 649 - 654. [Abstract] [Full Text] [PDF]

				M. L. Bots, D. Baldassarre, A. Simon, E. de Groot, D. H. O'Leary, W. Riley, J. J. Kastelein, and D. E. Grobbee Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur. Heart J., February 2, 2007; 28(4): 398 - 406. [Abstract] [Full Text] [PDF]

				S. Bonovas, K. Filioussi, N. Tsavaris, and N. M. Sitaras Statins and Cancer Risk: A Literature-Based Meta-Analysis and Meta-Regression Analysis of 35 Randomized Controlled Trials J. Clin. Oncol., October 20, 2006; 24(30): 4808 - 4817. [Abstract] [Full Text] [PDF]

				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]

				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]

This Article Abstract Full Text (PDF) All Versions of this Article: 35/12/2807    most recent 01.STR.0000147041.00840.59v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zanchetti, A. Search for Related Content PubMed PubMed Citation Articles by Zanchetti, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cholesterol High Blood Pressure Hazardous Substances DB HYDROCHLOROTHIAZIDE Related Collections Clinical Studies Lipids Cardiovascular Pharmacology Imaging Doppler ultrasound, Transcranial Doppler etc.