Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial

EARLY REPORTS

Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial Françoise Forette, Marie-Laure Seux, Jan A Staessen, Lutgarde Thijs, Willem H Birkenhäger, Marija-Ruta Babarskiene, Speranta Babeanu, Alfredo Bossini, Blas Gil-Extremera, Xavier Girerd, Tovio Laks, Emil Lilov, Valentine Moisseyev, Jaakko Tuomilehto, Hannu Vanhanen, John Webster, Yair Yodfat, Robert Fagard, on behalf of the Syst-Eur Investigators*

Summary Background Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebocontrolled Systolic Hypertension in Europe (Syst-Eur) trial, investigated whether antihypertensive drug treatment could reduce the incidence of dementia. Methods Eligible patients had no dementia, were at least 60 years old, and had a blood pressure when seated of 160–219 mm Hg systolic and below 95 mm Hg diastolic. Active treatment consisted of nitrendipine (10–40 mg/day) with the possible addition of enalapril (5–20 mg/day), hydrochlorothiazide (12·5–25 mg/day), or both drugs, titrated or combined to reduce the systolic blood pressure by at least 20 mm Hg to reach a value below 150 mm Hg. Cognitive function was assessed by the mini mental state examination (MMSE). If the MMSE score was 23 or less, diagnostic tests for dementia were done (DSMIII-R criteria). The cause of dementia was established by the modified ischaemic score with brain imaging or the Hachinski score. Findings Median follow-up by intention to treat was 2·0 years. Compared with placebo (n=1180), active treatment (n=1238) reduced the incidence of dementia by 50% from 7·7 to 3·8 cases per 1000 patient-years (21 vs 11 *Investigators listed at end of paper

Department of Geriatrics, Hôpital Broca, University of Paris V, Paris, France (Prof F Forette MD, M-L Seux MD); Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium (J A Staessen MD, L Thijs BSc, Prof R Fagard MD); Erasmus University, Rotterdam, Netherlands (Prof W H Birkenhäger MD); Institute of Cardiology, Kaunas, Lithuania (M-R Babarskiene MD); National Institute Ana Aslan, Bucharest, Romania (S Babeanu MD); Centro Ipertensione Policlinico Umberto I, Roma, Italy (A Bossini MD); Facultad de Medicina, Universidad de Granada, Granada, Spain (B Gil-Extremera MD); Department of Internal Medicine, Broussais Hospital, University of Paris V, Paris, France (X Girerd MD); Tallinn Central Hospital, Tallinn, Estonia (T Laks MD); Regional Health Center, Vidin, Bulgaria (E Lilov MD); Department of Internal Diseases, Municipal Clinical Hospital, Moscow, Russian Federation (Prof V Moisseyev MD); Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki (Prof J Tuomilehto MD); Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (H Vanhanen MD); University of Aberdeen, Aberdeen Royal Hospitals, Aberdeen, UK (J Webster MD); and Department of Family Medicine, Hadassah Medical School, Hebrew University of Jerusalem, Jerusalem, Israël (Prof Y Yodfat MD) Correspondence to: Prof Françoise Forette, Department of Geriatrics, Hôpital Broca, CHU Cochin, University Paris V, 54-56 rue Pascal, 75013 Paris, France (e-mail: franç[email protected])

THE LANCET • Vol 352 • October 24, 1998

patients, p=0·05). The median MMSE score at randomisation was 29 in both treatment groups. At the last available assessment, systolic and diastolic blood pressure were, respectively, 8·3 mm Hg and 3·8 mm Hg lower (p<0·001) in the active-treatment group, but on average the MMSE scores did not change in either group. In the control patients, however, the MMSE decreased (p=0·04) with decreasing diastolic blood pressure, whereas in the active-treatment group MMSE scores improved slightly (p=0·01) with greater reduction in diastolic blood pressure (p=0·002 for between-group difference). Interpretation In elderly people with isolated systolic hypertension, antihypertensive treatment was associated with a lower incidence of dementia. If 1000 hypertensive patients were treated with antihypertensive drugs for 5 years 19 cases of dementia might be prevented.

Lancet 1998; 352: 1347–51

Introduction In 1997 the Rotterdam Study showed that indicators of atherosclerosis, such as hypertension, were associated not only with vascular dementia, but also with Alzheimer’s disease.1 Although hypertension is the strongest risk factor for vascular dementia2 the placebo-controlled Systolic Hypertension in the Elderly Program (SHEP) study3 did not confirm the hypothesis that antihypertensive treatment, with chlortalidone, would reduce the incidence of dementia. As part of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial,4,5 the vascular dementia project aimed to investigate whether antihypertensive treatment starting with the calciumchannel blocker nitrendipine could prevent vascular dementia in older patients with isolated systolic hypertension. The Syst-Eur trial stopped on Feb 14, 1997, according to predefined stopping rules,5 because the second of four planned interim analyses had shown a significant benefit for stroke, the primary endpoint.4

Methods General design The protocol of the Syst-Eur trial, described elsewhere,4,5 was approved by the ethics committee of all participating centres. Eligible patients had to have no dementia, be at least 60 years old, and have a systolic blood pressure when seated of 160–219 mm Hg with diastolic blood pressure below 95 mm Hg. After stratification by centre, sex, and previous cardiovascular complications, the patients were randomly assigned double-blind treatment with active medication or placebo by means of a computerised random function.4,5 The study medications were titrated in a stepwise way and combined to reduce the systolic blood pressure by 20 mm Hg or more to below 150 mm Hg.

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EARLY REPORTS

Number of patients randomised

5000 Full trial Dementia project

4000

Feb 14, 1997 End of trial

Required sample size

3000

744 not included in analysis 7 ⬎5 MMSE items not answered 20 baseline MMSE not available 9 demented at baseline 16 baseline MMSE⭐23 and DSM-III-R not done 692 not evaluated because of early trial termination

Sept 10, 1996

2000 1000

3162 recruited

Jan 7, 1997 Last randomisation

Jan 31, 1990 End of pilot run

0 Jan 1, 1989

Jan 1, 1991

Jan 1, 1993

Jan 1, 1995

Jan 1, 1997

Figure 1: Number of patients randomised in full trial and in vascular dementia project Active treatment was initiated with nitrendipine (first-line medication, 10–40 mg/day). If necessary, the calcium-channel blocker was combined with or replaced by enalapril (second-line medication, 5–20 mg/day), hydrochlorothiazide (third-line medication, 12·5–25 mg/day), or both drugs. In the control group, matching placebos were used in a similar way. Patients withdrawing from double-blind treatment remained in open follow-up.

2418 included in analysis

1180 assigned placebo

989 in per-protocol analysis

1238 assigned active treatment

1180 in intention-totreat analysis

1072 in per-protocol analysis

1238 in intention-totreat analysis

Vascular dementia project

Figure 2: Trial profile

Syst-Eur investigators could opt to take part in the vascular dementia project.6 They screened all their patients for cognitive impairment at baseline and at annual follow-up visits, using the mini mental state examination (MMSE).7 This questionnaire assesses orientation in time and space, instantaneous recall, short-term memory, attention and calculation, constructional capacity, and language. Translations of the questionnaire into the many languages needed for the trial were validated by backtranslation into English. The 30 test items were each scored by one point if successfully completed; missing items received a zero score. Incapacitated patients unable to complete all 30 items received a proportional score with, as denominator, the total number of items answered. However, as outlined by the protocol,6 patients were excluded from analysis if a physical or visual handicap made their participation in more than five items impossible. In keeping with widely accepted conventions,8,9 patients whose MMSE score was 23 or less underwent further diagnostic examinations to ascertain the presence and type of dementia. These diagnostic tests were also done if incipient cognitive impairment was apparent from symptoms reported by the patient or relatives at follow-up, or clinical signs observed by the doctor, or if for any reason a planned MMSE questionnaire had not been administered. The diagnosis of dementia relied on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R),10 which when SystEur began in 1988 was the generally accepted standard.11–13 If the DSM-III-R criteria10 confirmed the diagnosis of dementia, the modified ischaemic score,14 including a brain scan by computed tomography (CT), served to differentiate vascular from degenerative disease. If a CT scan could not be done, the Hachinski score15 replaced the modified ischaemic score14 to establish the cause of dementia. At annual meetings the investigators were trained to administer the MMSE questionnaire6 and to implement the same diagnostic procedures. Moreover, all cases of dementia were validated by a review board unaware of treatment allocation. Two independent neuroradiologists checked all CT scans.

of 5 years was deemed sufficient to test the two-sided hypothesis of a 40% change in the incidence of dementia with 1% significance and 90% power.6 Database management and statistical analysis were done with SAS software, version 6·12. When the trial was stopped, the null hypothesis was tested, both by an intention-to-treat and by a perprotocol analysis. The latter included only the data collected while the patients were still on double-blind treatment. Means were compared by the standard normal z test and proportions by ␹2. The incidence of dementia was analysed by means of KaplanMeier survival-function estimates and the log-rank test. Correlations between the changes in the MMSE scores and blood pressure were calculated from the differences from baseline to the last available follow-up measurement.17 The statistical methods also included multiple linear regression and stepwise Cox regression.

Statistical analysis Based on epidemiological studies in hypertensive patients,16 the original sample-size calculations assumed that the rate of dementia in the placebo group would be 16 cases per 1000 patient-years. A total of 3000 patients with an average follow-up

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Results At 106 centres in 19 European countries 3162 patients were enrolled. However, owing to the early termination of Characteristic

Treatment group Placebo (n=1180)

Active treatment (n=1238)

Mean (SD) age (years)

69·9 (6·2)

69·9 (6·5)

Mean (SD) body-mass index (kg/m2)

27·0 (4·0)

27·0 (4·2)

Mean (SD) blood pressure (mm Hg)* Systolic Diastolic

173·4 (10·1) 86·0 (5·7)

173·5 (10·1) 86·1 (5·6)

Mean (SD) age on leaving school (years)

16·2 (4·4)

16·4 (4·7)

Median (range) MMSE score

29 (15–30)

29 (18–30)

Number of patients with characteristic at randomisation Women 767 (65·0%) Previous antihypertensive medication 476 (40·3%) Cardiovascular complications 337 (28·6%) Atrial fibrillation 44 (3·7%) MMSE score=30 350 (29·7%) MMSE score 聿23 23 (1·9%)

822 (66·4%) 467 (37·7%) 340 (27·5%) 46 (3·7%) 360 (30·4%) 24 (1·9%)

*Average of six measurements when seated: two at each of three baseline visits 1 month apart.

Table 1: Clinical features of treatment groups at randomisation

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EARLY REPORTS

Characteristic

Placebo

Active treatment

All patients

Intention-to-treat analysis* Patient-years of follow-up All cases Alzheimer’s dementia Mixed dementia Vascular dementia

2737 21 15 4 2

2885 11 8 3 0

5622 32 23 7 2

Per-protocol analysis† Patient-years of follow-up All cases Alzheimer’s dementia Mixed dementia Vascular dementia

2260 15 13 2 0

2634 7 5 2 0

4894 22 18 4 0

and 462 (54%), respectively, also received enalapril or enalapril-placebo; and 150 (15%) and 272 (32%), respectively, proceeded to hydrochlorothiazide or its placebo (table 3). Of the 104 active-group patients and 199 placebo-group patients in open follow-up, 72 (69%) and 144 (72%) were on open-label antihypertensive drugs. Among the 11 patients in the active-treatment group in the intention-to-treat analysis who developed dementia, seven remained on monotherapy with nitrendipine and three had proceeded to combined treatment with nitrendipine, enalapril, and hydrochlorothiazide; in one patient treatment was unknown. At the last available measurement, systolic and diastolic blood pressure had fallen (p<0·001) by a mean of 13·4 mm Hg (SD 16·2) and 2·6 mm Hg (7·8) in the placebo group and by 21·7 mm Hg (16·2) and 6·4 mm Hg (8·3) in the active-treatment group. The between-group differences (p<0·001) were 8·3 mm Hg systolic (95% CI 7·0–9·6) and 3·8 mm Hg diastolic (3·2–4·5). The last MMSE score (median) was 29 in both groups (5th–95% percentile interval 24–30). The change from the score at randomisation averaged 0·01 (2·15) points (p=0·87) in the placebo group and 0·08 (1·76) points (p=0·12) in the active-treatment group (between-group difference 0·07 [95% CI ⫺0·09 to 0·23]; p=0·40). In the placebo group, the MMSE score decreased when systolic or diastolic blood pressure decreased (figure 3), whereas in the active-treatment group the scores remained unchanged or improved slightly; the between-group differences in these associations were significant for systolic (p=0·03) and diastolic (p=0·002) blood pressure. In stepwise Cox regression, after adjustment for active treatment, the risk of dementia was increased by 89% (95% CI 45–147, p<0·001) for being 5 years older or by 40% (25–57, p<0·001) for having a one point lower MMSE score at entry. The following variables measured at entry were not identified as independent predictors of dementia: sex, age on leaving school, systolic blood pressure, previous cardiovascular complications, antihypertensive drug treatment before enrolment, atrial fibrillation, smoking, and alcohol consumption.

Number of cases except for patient-years of follow-up. *Includes dementia cases occurring during double-blind and open follow-up. †Includes only dementia cases occurring during double-blind treatment.

Table 2: Aetiology of dementia

the trial (figure 1), 692 patients did not accumulate 1 year of follow-up and their cognitive function was therefore not taken into account in this assessment (figure 2). In addition, 52 patients were excluded (figure 2). Thus, the number of patients for the present analysis totalled 2418. At randomisation, the patients allocated placebo (n=1180) and those allocated active treatment (n=1238) had similar characteristics (table 1). Among the 32 incident cases of dementia in the intention-to-treat analysis, 23 were Alzheimer’s disease and only two were vascular dementia (table 2). Only one patient randomised to placebo had a stroke and subsequently developed vascular dementia. However, none of the other demented patients had experienced a stroke before or after randomisation. There were 21 cases in the placebo group and 11 in the active-treatment group. The number of patient-years was 2737 and 2885, respectively (median follow-up 2·0 years). Active treatment reduced the rate of dementia by 50% (95% CI 0–76) from 7·7 to 3·8 cases per 1000 patient-years (p=0·05). In the per-protocol analysis (table 2), active treatment decreased the rate by 60% (2–83) from 6·6 to 2·7 cases per 1000 patient-years (p=0·03). At the final visit, 1861 patients remained on doubleblind treatment (1000 on active treatment and 861 on placebo): 602 (60%) remained on nitrendipine only and 347 (40%) remained on nitrendipine-placebo; 315 (32%) Characteristic

Patients with MMSE Total MMSE during double-blind follow-up No study drugs Nitrendipine/placebo only Study drugs other than nitrendipine Treatment unknown Drugs taken* Nitrendipine/placebo Enalapril/placebo Hydrochlorothiazide/placebo Other antihypertensive drugs† MMSE during open follow-up Patients without MMSE Total Cognitive evaluation not done Only DSM-III-R done Died Non-supervised open follow-up Lost to follow-up‡

Placebo

Active treatment

Year 1 (n=1180)

Year 2 (n=872)

Year 3 (n=615)

Year 4 (n=456)

Final visit (n=1180)

Year 1 (n=1238)

Year 2 (n=890)

Year 3 (n=649)

Year 4 (n=473)

Final visit (n=1238)

1003 951 1 496 450 4

640 542 2 212 327 1

419 333 0 105 227 1

285 200 0 54 145 1

1060 861 1 347 508 5

1052 1026 0 713 308 5

685 636 4 375 257 0

441 394 0 220 172 2

314 262 2 129 131 0

1104 1000 6 602 389 3

907 419 183 14 52

496 293 191 5 98

299 202 141 5 86

176 131 101 2 85

800 462 272 11 199

915 264 85 8 26

534 195 114 9 49

330 122 101 4 47

212 94 73 3 52

854 315 150 4 104

177 134 2 13 20 8

232 153 1 21 26 31

196 101 2 26 43 24

171 72 1 27 48 23

120 77 2 13 20 8

186 137 3 8 20 18

205 114 3 21 41 26

208 105 3 26 46 28

159 70 2 26 45 16

134 84 4 8 20 18

*In active-treatment group, mean (SD) daily doses of nitrendipine, enalapril, and hydrochlorothiazide at final visit were 28 (12) mg, 13 (6) mg, and 22 (5) mg, respectively. In placebo group matching placebos were used. Because many patients were on combined treatment, numbers do not add up. †To cover medical emergencies without having to break code, antihypertensive drugs could be prescribed during double-blind study period for up to 3 consecutive months. ‡For patients without follow-up data for more than 1 year, last available results were used in analysis

Table 3: Follow-up and treatment status by treatment group and year of follow-up in the dementia project

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EARLY REPORTS

Change in MMSE score (points)

0·3

Change in systolic pressure

Change in diastolic pressure

p=0·01

Placebo Active treatment

0 p=0·04 p=0·53

p=0·001

–0·3

p=0·002 p=0·03 Figure 3: Changes in MMSE score associated with mean decrease in systolic and diastolic blood pressure in placebo and active treatment groups Association sizes adjusted for sex, age, educational level, previous cardiovascular complications, antihypertensive treatment before enrolment, smoking, and alcohol consumption at randomisation.

Discussion In elderly patients with isolated systolic hypertension, active treatment starting with the dihydropyridine calcium-channel blocker nitrendipine halved the rate of dementia from 7·7 to 3·8 cases per 1000 patient-years. Selective recruitment of relatively healthy patients who would accept long-term follow-up in a double-blind trial is likely to explain the high MMSE scores (median 29 points) at entry and the low incidence of dementia in the placebo group (7·7 per 1000 patient-years), compared with population-based studies.11–13 For instance, in the Eurodem study,12 the incidence of dementia was 10 per 1000 patient-years. For this reason, as well as because of the early termination of the double-blind part of the SystEur trial,5 our findings, however favourable, probably underestimate the potential prevention of dementia by antihypertensive treatment. The Syst-Eur trial started in 1988. At that time, the DSM-III-R examination10 was the most up-to-date diagnostic criteria for dementia. They were well accepted by the international scientific community and were applied in important epidemiological studies.11–13 The Syst-Eur patients were therefore examined according to these criteria.10 The criteria of Chui and colleagues18 NINCDS-AIREN19 and the DSM-IV20 were published after Syst-Eur began. Diagnostic rules defined before a trial begins6 cannot be changed when it is underway. Moreover, Erkinjuntti and colleagues21 found that compared with the more modern diagnostic tests for dementia, the DSM-III-R criteria10 conferred a low risk of overdiagnosis or underdiagnosis. Thus, the development of newer diagnostic criteria is unlikely to detract from the overall validity of our findings. By the same token, this randomised, double-blind, placebo-controlled trial meets the requirements called for by Heckbert and colleagues22 in their interpretation of a possible deleterious effect of calcium-channel blockade on cognitive function that was noticed in a non-randomised study.22 This study was not designed to elucidate the mechanism of dementia prevention, but its primary hypothesis was that a reduction in blood pressure would 1350

protect against vascular dementia.6 In keeping with this hypothesis, the MMSE scores improved slightly with decreasing diastolic blood pressure in the activetreatment group. The decrease in incidence of Alzheimer’s disease was unexpected, although some studies have shown that vascular factors, particularly hypertension, may have a role in the development of degenerative dementias as well as vascular dementia itself.1 On the other hand, the observation that antihypertensive (thiazide) treatment did not protect against cognitive impairment in the SHEP trial3 suggests that dementia cannot be prevented simply just by lowering of blood pressure. In vascular and degenerative dementias the calcium-channel blocker nimodipine, compared with placebo, slightly improved the MMSE scores.23 Thus, an additional or alternative explanation, albeit still unproven, could be that specific neuroprotection is conferred by calcium-channel blockade.23–25 The ageing brain loses its ability to regulate intracellular calcium, leading to a cascade of cellular impairments and, ultimately, cell death.24,25 In patients with Alzheimer’s disease, ␤-amyloid may raise the concentration of intraneuronal free calcium and through this mechanism may sensitise the brain to neurotoxins, such as proinflammatory substances or pro-oxidants.25 The hypothesis of a possible central nervous action of nitrendipine is also supported by the observation that this drug crosses the blood-brain barrier and decreases the turnover of monoamine neurotransmitters,26 many of which are deficient in degenerative dementias.25 Nitrendipine binding in the rat brain also occurs mainly at those sites that are primarily affected by Alzheimer’s disease, such as the superficial cortex, thalamus, and hippocampus, and not in areas with low synaptic density.27 The potential reduction by 50% of the incidence of dementias by antihypertensive drug treatment, initiated with the dihydropyridine nitrendipine, may have important public-health implications in view of the increasing longevity of populations worldwide. At the rate observed in the placebo group, treatment of 1000 hypertensive patients for 5 years could prevent 19 cases; the benefit could even be larger in unselected higher-risk groups. This beneficial outcome is in addition to the 53 major cardiovascular endpoints similarly prevented by the active drugs used in the Syst-Eur trial.5 Contributors Françoise Forette and Marie-Laure Seux designed and coordinated the vascular dementia project and wrote the first draft of the paper together with Jan A Staessen, Willem H Birkenhäger, and John Webster. Robert Fagard and Jan A Staessen coordinated the Syst-Eur trial. Lutgarde Thijs managed the database and did the statistical analysis. Marija-Ruta Babarskiene, Speranta Babeanu, Alfredo Bossini, Blas Gil-Extremera, Xavier Girerd, Tovio Laks, Emil Lilov, Valentine Moisseyev, Jaakko Tuomilehto, Hannu Vanhanen, and Yair Yodfat participated in annual meetings to discuss the practical implementation of the protocol, the training of the observers, and assured the quality control of the data collected in their respective countries. All named investigators took part in the interpretation of the results and prepared the final draft of the paper.

Acknowledgments The Syst-Eur vascular dementia project was a concerted action of the European Union’s Biomed Research Programme and was conducted under the auspices of the Fondation Nationale de Gérontologie (France). The Syst-Eur trial was carried out in consultation with WHO, the International Society of Hypertension, the European Study of Hypertension, and the World Hypertension League. The Syst-Eur trial was supported by Bayer AG (Wuppertal, Germany). The study medication was donated by Bayer AG and Merck Sharpe and Dohme (West Point, PA, USA). Additional grants in support of the vascular

THE LANCET • Vol 352 • October 24, 1998

EARLY REPORTS dementia project were provided by the Belgian National Research Fund (Brussels, Belgium), Specia SA (Paris, France), and INSERM (Paris, France).

Syst-Eur Investigators involved in vascular dementia project Belgium—J Claus, E De Graef, H Dieu, R Fagard, P Gilbert, J Gremling, W Pelemans. Bulgaria—M Grigorov, K Janculova, E Lilov, J Nachev, T Tchernev, T N Vasileva. Czech Republic—J Filipovsky. Estonia—T Laks. Finland—M Alaluoto, R Antikainen, M Haapio, T Hakamäki, K Halonen, M Jääskivi, P Kivinen, P P Kohohnen-Jalonen, P Kuusisto, E Lehmus, E Lehtomäki, A Lehtonen, R Tilvis, E Ruotsalainen, H Vanhanen, O Vänskä, S Vinni, H Virtanen, H Wallinheimo. France—P Berger, F Bezot, L Boucher, J Boussac, A Campagne, C Copere, R Corlier, E De Saint Lorette, G Donnarel, M Escande, G Etchegaray, H Feuillette, Y M Flores, F Forette, G François, X Girerd, M Grégoire, S Houdrie-Pavie, J R Israel, J B Leblond, I Périlliat, M Masieri, C H Mercier, G Meridjen, Y Ollivier, L M Pommier, E Quignard, P Romejko, M Safar, J M Vigne. Greece—A D Efstrapoulos. Ireland—L Bradley, J Duggan, F Mee, E T O’Brien. Israël—J Fidel, A Goldhaber, I Moran, J R Viskoper, Y Yodfat. Italy—A Bossini, G Maiorano, C Pasotti, P Palatini, A Pirelli, L Terzoli. Lithuania—M R Babarskiene. Netherlands—A J Man In’t Veld, H Stom, A H van den Meiracker, J M J Van Der Cammen, N Vogel, J Woittiez. Poland—J Kocemba. Portugal—M Carrageta, G Leiria. Romania—S Babeanu, V Bogdaneanu, L Serban. Russian Federation—G G Arabidze, A Y Ivleva, V Moissseyev. Slovakia—Z Gérová. Spain—B Gil-Extremera, A Maldonado-Martin, R Marin, F Vega, R Navarro, V Cuesta, J O Martinez, A R Bataro, J O Pujadas, J Mora-Macia, J L Rodicio, L M Ruilope. UK—M Beevers, C Davidson, P Gunawardena, A O’Brien, J Webster, J C Petrie, P R Wilkinson.

6

7

8

9

10

11

12 13

14

Committees and coordination Coordinators of vascular dementia project—F Forette, M L Seux, T Strasser. Vascular dementia project review board—A Alpérovitch, F Boller, M M Dubs, F Forette, D Furet, M-L Seux, L Traykoff. Liaison committee with the European Union—W H Birkenhäger, F De Padua, C T Dollery, A D Efstratopoulos, R Fagard, F Forette, D Ganten, E T O’Brien, K O’Malley, J L Rodicio, J Tuomilehto, C van Ypersele, A Zanchett. Trial Coordinators—R Fagard, J A Staessen. Data monitoring committee—C J Bulpitt, A E Fletcher, J A Staessen, L Thijs. Endpoint committee—P W de Leeuw, R Fagard, G Leonetti, J Petrie, H Vanhanen. Ethics committee—W H Birkenhäger, C T Dollery, R Fagard. Publication committee—W H Birkenhäger, C J Bulpitt, J A Staessen, A Zanchetti. Steering committee—P De Cort, R Fagard, F Forette, K Kawecka-Jaszcz, G Leonetti, C Nachev, E T O’Brien, J L Rodicio, J Rosenfeld, J Tuomilehto, J Webster, Y Yodfat. Coordination of general practices—H Celis in collaboration with J Heyrman, G Stibbe, M Van den Haute, Y Yodfat. Coordinating office—N Ausloos, H Celis, L De Pauw, P Drent, J Gasowski, R Fagard, H Fan, V Mariën, J A Staessen, L Thijs, S Vandenreyken, R Van Hoof, S Van Hulle, R Wolfs.

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2 3

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5

Hofman A, Ott A, Breteler MMB, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer’s disease in the Rotterdam Study. Lancet 1997; 349: 151–54. Forette F, Boller F. Hypertension and risk of dementia in the elderly. Am J Med 1991; 90: 14S–19S. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64. Amery A, Birkenhäger W, Bulpitt CJ, et al. Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization. Aging Clin Exp Res 1991; 3: 287–302. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind

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