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Subgroup and Per-Protocol Analysis of the Randomized European Trial on Isolated Systolic Hypertension in the Elderly
Jan A. Staessen, MD;
Robert Fagard, MD;
Lutgarde Thijs, BSc;
Hilde Celis, MD;
Willem H. Birkenhäger, MD;
Christopher J. Bulpitt, MD;
Peter W. de Leeuw, MD;
Astrid E. Fletcher, PhD;
Marija-Ruta Babarskiene, MD;
Françoise Forette, MD;
Josef Kocemba, MD;
Tovio Laks, MD;
Gastone Leonetti, MD;
Choudomir Nachev, MD;
James C. Petrie, MD;
Jaakko Tuomilehto, MD;
Hannu Vanhanen, MD;
John Webster, MD;
Yair Yodfat, MD;
Alberto Zanchetti, MD;
for the Systolic Hypertension in Europe Trial Investigators
Arch Intern Med. 1998;158:1681-1691.
Background In 1989, the European Working Party on High Blood Pressure in the Elderly started the double-blind, placebo-controlled, Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension. This report addresses whether the benefit of antihypertensive treatment varied according to sex, previous cardiovascular complications, age, initial blood pressure (BP), and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per-protocol analysis.
Methods After stratification for center, sex, and cardiovascular complications, 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were randomized. Active treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d) and/or hydrochlorothiazide (12.5-25 mg/d), titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg, to below 150 mm Hg. In the control group, matching placebo tablets were employed similarly.
Results In the intention-to-treat analysis, male sex, previous cardiovascular complications, older age, higher systolic BP, and smoking at randomization were positively and independently correlated with cardiovascular risk. Furthermore, for total (P=.009) and cardiovascular (P=.09) mortality, the benefit of antihypertensive drug treatment weakened with advancing age; for total mortality (P=.05), the benefit increased with higher systolic BP at entry, while for fatal and nonfatal stroke (P=.01), it was most evident in nonsmokers (92.5% of all patients). In the per-protocol analysis, active treatment reduced total mortality by 24% (P=.05), reduced all fatal and nonfatal cardiovascular end points by 32% (P<.001), reduced all strokes by 44% (P=.004), reduced nonfatal strokes by 48% (P=.005), and reduced all cardiac end points, including sudden death, by 26% (P=.05).
Conclusions In elderly patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular end points, 29 strokes, or 25 cardiac end points. The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients.
From the Department of Cardiovascular and Molecular Research, University of Leuven, Belgium (Drs Staessen, Fagard, Thijs, and Celis); Erasmus University, Rotterdam, the Netherlands (Dr Birkenhäger); Department of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, England (Dr Bulpitt); Department of Internal Medicine, University Hospital of Maastricht, the Netherlands (Dr de Leeuw); Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine (Dr Fletcher); Institute of Cardiology, Kaunas, Lithuania (Dr Babarskiene); Department of Geriatrics, Hôpital Broca, University of Paris, France (Dr Forette); Clinic of Geriatric Medicine, Jagiellonian University, Cracow, Poland (Dr Kocemba); Department of Clinical Physiology, Mustamäe Hospital, Tallin, Estonia (Dr Laks); Istituto Auxologico Italiano, Istituto Scientifico San Luca, and Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggiore, University of Milan, Italy (Drs Leonetti and Zanchetti); Department of Internal Medicine, Alexandrov's University Hospital, Sofia, Bulgaria (Dr Nachev); Department of Medicine and Therapeutics, University of Aberdeen, Scotland (Drs Petrie and Webster); Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (Dr Tuomilehto); Department of Medicine, Division of Geriatrics, Helsinki University Central Hospital, Helsinki (Dr Vanhanen); and Department of Family Medicine, Hadassah Medical School, Jerusalem, Israel (Dr Yodfat).
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