Published Online
on October 28, 2004

A more recent version of this article appeared on December 1, 2004

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Submitted on June 21, 2004
Revised on August 24, 2004
Accepted on September 16, 2004

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.).

^* To whom correspondence should be addressed. E-mail: alberto.zanchetti{at}unimi.it.

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

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