Subgroup and Per-Protocol Analysis of the Randomized European Trial on Isolated Systolic Hypertension in the Elderly FREE

IN 1989, the European Working Party on High Blood Pressure in the Elderly started the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke.¹ Active treatment was initiated with the dihydropyridine calcium channel blocker nitrendipine,² with the possible addition of enalapril, hydrochlorothiazide, or both drugs. In the recently published intention-to-treat analysis of the Syst-Eur trial,³ active treatment decreased the overall stroke rate from 13.7 to 7.9 end points per 1000 patient-years (−42%, P =.003) and the incidence of all cardiovascular complications from 33.9 to 23.3 end points per 1000 patient-years (−31%, P<.001). At the rates observed in the placebo group, treating 1000 patients for 5 years could prevent 29 strokes or 53 major cardiovascular end points.³ Whereas analysis by intention to treat reduces bias due to selective withdrawals, it may underestimate the true effects of treatment by including all end points in the calculations, regardless of whether they occurred on randomized therapy or on open-label medication.

This article expands the first Syst-Eur report.³ It explores (1) whether the benefits of active treatment were evenly distributed across 4 strata, prospectively defined according to sex and previous cardiovascular complications¹; (2) whether the morbidity and mortality results were influenced by age, level of initial blood pressure, or smoking or drinking habits at randomization; and (3) whether the estimates of benefit remained consistent, if instead of an intention-to-treat approach, a per-protocol approach was applied.

The protocol of the Syst-Eur trial^1,3 was approved by the ethics committees of the University of Leuven, Belgium, and the participating centers and implemented according to the principles outlined in the Helsinki declaration.⁴ Patients were eligible (1) if they were at least 60 years old; (2) if on placebo during the run-in phase their sitting systolic blood pressure ranged from 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg; (3) if their standing systolic blood pressure was 140 mm Hg or more; (4) if they consented to be enrolled; and (5) if long-term follow-up was possible. The blood pressure criteria for entry were based on the averages of 6 sitting and 6 standing readings, ie, 2 in each position at 3 baseline visits 1 month apart. Patients could not be enrolled if systolic hypertension was secondary to a disorder that needed specific medical or surgical treatment. Other exclusion criteria were retinal hemorrhage or papilledema; congestive heart failure; dissecting aortic aneurysm; a serum creatinine concentration at presentation of 180 µmol/L (2 mg/dL) or higher; a history of severe nosebleeds, stroke, or myocardial infarction in the year before the study; dementia or substance abuse; any condition prohibiting a sitting or standing position; or severe concomitant cardiovascular or noncardiovascular disease.

Eligible patients were prospectively stratified by center, sex, and previous cardiovascular complications and thereafter randomized to double-blind treatment with active medication or placebo by means of a computerized random function. Patients with a Sokolow-Lyon electrocardiographic voltage index of 35 mm or more⁵ were included in the group with cardiovascular complications at entry. After randomization, active treatment was initiated with nitrendipine (10-40 mg/d). If necessary, the calcium channel blocker was combined with or replaced by enalapril maleate (5-20 mg/d) or hydrochlorothiazide (12.5-25 mg/d) or both drugs. The patients in the control group received matching placebos. The study medications were stepwise titrated and combined to reduce sitting systolic blood pressure by 20 mm Hg or more to less than 150 mm Hg.¹ Patients withdrawing from double-blind treatment remained in open follow-up.¹ During double-blind treatment and supervised open follow-up, clinic visits were scheduled at 3-month intervals. For patients who withdrew from double-blind treatment and for whom regular follow-up was impossible, information was collected annually (nonsupervised open follow-up). Patients without any report within the year before the trial stopped were counted as unavailable for follow-up but were included in the analysis up to the most recent evaluation of their health status.

The End Point Committee, which was unaware of the patients' treatment, identified all major end points by reviewing the patients' files and other source documents, by requesting detailed written information from the investigators, or by both approaches. Diseases were coded according to the International Classification of Diseases, Ninth Revision (ICD-9).⁶

Stroke, the primary end point in the Syst-Eur trial, was defined as a neurologic deficit continuing for more than 24 hours or leading to death with no apparent cause other than vascular. The diagnosis of acute myocardial infarction rested on 2 of the following 3 disorders: typical chest pain, electrocardiographic changes, or increased cardiac enzyme levels. Myocardial infarction did not include silent myocardial infarction. Congestive heart failure required the presence of 3 conditions, namely, symptoms, such as dyspnea; clinical signs, such as ankle edema or rales; and the necessity of treatment with diuretics, vasodilators, or antihypertensive drugs. Sudden death included any death of unknown origin occurring instantly or within 24 hours of the onset of acute symptoms, as well as unattended death for which no likely cause could be established by autopsy or recent medical history. Cardiac end points included fatal and nonfatal heart failure, fatal and nonfatal myocardial infarction, and sudden death.

Database management and statistical analysis were performed with SAS software (SAS Institute Inc, Cary, NC). Only 2-sided statistical tests were used. Comparisons of means and proportions relied on the standard normal z test and the χ² statistic, respectively. Relative risk was assessed by single and multiple Cox regression.⁷ Survival curves were compared using Kaplan-Meier survival function estimates and the log-rank test. The analysis by intention to treat included all end points occurring during double-blind and open follow-up, regardless of whether the patients were taking the treatment to which they had been randomized. The per-protocol analysis included only the end points that intervened during the double-blind phase of the trial.

In the 4695 randomized patients (Figure 1) the median follow-up by intention to treat was 2.0 years (range, 1-97 months). The numbers of patient-years in the placebo and active treatment groups were 5709 and 5995, respectively. At median follow-up, the sitting systolic and diastolic blood pressures had fallen by a mean (±SD) of 13±17 and 2±8 mm Hg, respectively, in the placebo group and by 23±16 and 7±8 mm Hg in the active treatment group. The differences in systolic and diastolic blood pressures between the 2 groups then averaged 10.1 mm Hg (95% confidence interval [CI], 8.8-11.4 mm Hg) and 4.5 mm Hg (95% CI, 3.9-5.1 mm Hg), respectively. The analysis by intention to treat, both before (Table 1) and after (Table 2) adjustment for significant covariates, showed that active treatment had reduced the incidence of fatal and nonfatal stroke (P<.01), fatal and nonfatal cardiac complications (P<.05), and all fatal and nonfatal cardiovascular end points (P<.001). Cardiovascular mortality also showed a tendency to decrease (P=.07).

Before randomization, the patients had been prospectively stratified by sex and previous cardiovascular complications. The trial included 1557 men (33.2%), 3138 women (66.8%), 1402 patients with previous cardiovascular complications (29.9%), and 3293 patients without such complications (70.1%). The 4 strata were equally represented in the 2 arms of the trial. Most cardiovascular complications at randomization were mild. Only 58 patients (4.1% of those with cardiovascular complications) had a history of stroke and 163 (11.6%) a history of myocardial infarction. The other patients with cardiovascular complications at entry had symptoms or signs suggestive of coronary heart disease (n=412), symptoms or signs of cerebrovascular disease (n=45), electrocardiographic changes compatible with left ventricular hypertrophy (n=614), or a combination of these conditions or other vascular, retinal, or renal lesions (n=110).

Men and patients with cardiovascular complications at entry experienced significantly more end points during follow-up (Table 1). With adjustments applied for the covariates listed in Table 2, male sex did not behave as a significant predictor of fatal and nonfatal stroke (relative hazard rate [RHR], 1.17; 95% CI, 0.81-1.70; P =.40) or of fatal and nonfatal cardiac end points (RHR, 1.28; 95% CI, 0.95-1.17; P=.10). Further analysis showed that the benefits of active treatment were evenly distributed across the sex and cardiovascular complication groups. In multiple Cox regression, the P values for the interactions with treatment ranged from .62 to .86 for sex and from .26 to .87 for cardiovascular complications.

Age at randomization averaged 70.2 (6.7) years. In single (Table 1) and multiple (Table 2) regression, age was a strong predictor of outcome. Plots of the crude RHRs in 3 age strata (60-69, 70-79, and ≥80 years) suggested that for total and cardiovascular mortality (Figure 2) but not for the combined fatal and nonfatal end points (Figure 3), the effects of active treatment were attenuated in patients over the age of 80 years. In Cox regression (Figure 4), with adjustments applied for the significant covariates listed in Table 2, the treatment×age interaction term was significant (P=.009) for total mortality (RHR, 1.04; 95% CI, 1.01-1.08) and nearly significant (P=.09) for cardiovascular mortality (RHR, 1.04; 95% CI, 0.99-1.09). In contrast, the treatment×age interaction terms for the combined fatal and nonfatal end points were not statistically significant (Figure 5).

At randomization, the sitting blood pressure averaged 173.8±10.0 mm Hg systolic and 85.5±5.9 mm Hg diastolic. In single regression (Table 1), all end points except fatal and nonfatal cardiac complications were positively correlated with systolic blood pressure. However, after adjustment for the covariates listed in Table 2, systolic blood pressure predicted only stroke incidence. Plots of the crude RHRs in 3 strata according to the systolic blood pressure at randomization (160-169, 170-179, and ≥180 mm Hg) did not show a consistent trend (Figure 2 and Figure 3). However, for total mortality, after adjustment for significant covariates (Table 2), the treatment×systolic blood pressure interaction term was significant (P=.05) and suggested greater benefit at higher initial systolic blood pressure (Figure 4).

In single regression (Table 1), a higher diastolic blood pressure was associated with lower total (P<.001) and cardiovascular (P<.001) mortality and fewer combined fatal and nonfatal end points (P, <.001 to .02). However, after adjustment for the significant covariates listed in Table 2, these associations weakened to a nonsignificant level (P, .16 to .93) and were not influenced by treatment status (P, .14 to .82).

Of the 4695 patients, 1994 (42.5%) had been recruited in Eastern Europe (Belorussia, Bulgaria, Croatia, Czech Republic, Estonia, Lithuania, Poland, Romania, Slovakia, Slovenia, Russian Federation), where after adjustment for significant covariates (Table 2), total mortality was significantly higher than in Western Europe (Belgium, Finland, France, Germany, Greece, Ireland, Italy, the Netherlands, Portugal, Spain, United Kingdom) and Israel. Furthermore, with these adjustments applied, the interaction term with active treatment was nonsignificant (P=.53). This was also the case for cardiovascular (P=.08) mortality and the other combined fatal and nonfatal end points (P, .34 to .61).

At randomization, the median daily use of tobacco was 15 cigarettes in 231 male smokers (5th-95th percentile, 3-50 cigarettes) and 10 cigarettes (5th-95th percentile, 2-30 cigarettes) in 112 female smokers. Both before (Table 1) and after (Table 2) adjustment for significant covariates, smoking predicted total and cardiovascular mortality and combined fatal and nonfatal cardiovascular and cardiac end points. With adjustments for significant covariates (Table 2), Cox regression showed a significant interaction for stroke (P=.01) between treatment and smoking. The RHR for active treatment compared with placebo was 0.47 (95% CI, 0.32-0.69) in nonsmokers but 2.75 (95% CI, 0.73-10.4) in smokers. The percentage of smokers was similar among the stroke patients (8.9% [11/124]) and the other participants (7.3% [332/4571]).

At randomization, 393 men and 132 women consumed at least 1 U/d of an alcoholic beverage, ie, 1 glass of beer, wine, aperitif, fortified wine, or liquor. Their median daily consumption of alcohol was 19 g (5th-95th percentile: 10-54 g) and 14 g (5th-95th percentile: 10-36 g), respectively. Alcohol intake was not correlated with outcome either before (Table 1) or after (Table 2) adjustment for covariates (P, .14 to .64 and .19 to .85, respectively). In multiple Cox regression, P values for the interaction terms between treatment and drinking alcohol ranged from .16 to .99.

In the per-protocol analysis, the number of patient-years in the placebo and active treatment groups amounted to 4508 and 5166, respectively. The median follow-up was 1.7 years (range, 1-95 months). In the placebo and active treatment groups, 1235 and 1285 patients had a follow-up of 2 years or more, and 866 and 1014 were still in double-blind follow-up at 2 years (70.1% vs 78.9%, P<.001). Of the actively treated patients in double-blind follow-up, 856 (84.4%) were taking nitrendipine (mean daily dose, 28.2 mg), 330 (32.6%) enalapril maleate (13.8 mg/d), and 164 (16.2%) hydrochlorothiazide (21.2 mg/d). In the placebo group, these numbers were 800 (92.4%), 477 (55.1%), and 297 (34.2%), respectively. At median follow-up, the sitting systolic and diastolic blood pressures had fallen by 13±16 and 2±7 mm Hg, respectively, in the placebo group and by 25±15 and 7±8 mm Hg in the active treatment group. The between-group differences in sitting systolic and diastolic blood pressures then averaged 11.6 mm Hg (95% CI, 10.1-13.0 mm Hg) and 5.3 mm Hg (95% CI, 4.5-6.0 mm Hg), respectively.

Of the patients remaining on double-blind medication, 84 died in the placebo group and 71 in the active treatment group. The cumulative total mortality in the per-protocol analysis amounted to 18.6 and 13.7 deaths per 1000 patient-years, respectively (Table 3). Active treatment reduced total mortality by 26% (P=.05). A similar trend was observed for fatal myocardial infarction (−60%, P =.08). Although cerebrovascular (−31%, P =.36) and cardiac (−20%, P =.34) mortality rates were lower on active treatment, the wide confidence intervals for these fatal outcomes did not exclude the possibility of no effect of antihypertensive drug treatment.

In general, the per-protocol analysis of the nonfatal end points and the combined fatal and nonfatal end points produced results similar to those in the intention-to-treat approach (Table 4). Among the patients who remained in double-blind follow-up, active treatment reduced total stroke by 44% (P=.004) and nonfatal stroke by 48% (P=.005). In the active treatment group, nonfatal cardiac end points decreased by 29% (P=.07). A similar trend was observed for fatal and nonfatal cases of heart failure (−35%, P =.06). All fatal and nonfatal cardiac end points, including sudden death, declined by 26% (P=.05). Active treatment reduced all fatal and nonfatal cardiovascular end points by 32% (P<.001).

In terms of absolute benefit, the per-protocol analysis suggested that at the rates observed in the placebo group, treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular end points, 29 fatal and nonfatal strokes, 24 nonfatal strokes, 25 fatal and nonfatal cardiac end points, or 18 nonfatal cardiac end points.

Stratification by sex and previous cardiovascular complications allowed us to test whether these characteristics had influenced outcome in the Syst-Eur trial. As expected, men were at higher risk than women. Voltage criteria compatible with left ventricular hypertrophy⁵ accounted for the majority of cardiovascular complications at entry. Subjects stratified into this group died or experienced major cardiovascular end points at nearly twice the rate observed in the other patients. Men and women and patients with and without previous cardiovascular complications all benefited from antihypertensive drug treatment.

The interaction terms between active treatment and age suggested that antihypertensive drug treatment did not postpone death in patients older than 75 to 80 years (Figure 4) but probably still prevented cardiovascular complications, stroke, and cardiac end points in the very old (Figure 5). Age at recruitment ranged from 60 to 96 years in 6 randomized outcome trials^8- 13 of antihypertensive drug treatment (for a review, see Thijs et al¹⁴). In the trial conducted by the European Working Party on High Blood Pressure in the Elderly (EWPHE), a significant (P=.05) treatment×age interaction suggested that cardiovascular mortality decreased less on active treatment in the oldest patients, especially beyond 80 years.¹⁵ In the Swedish Trial in Old Patients With Hypertension (STOP-Hypertension),¹⁰ compared with the control group, older patients randomized to active treatment experienced less reduction in deaths from stroke, myocardial infarction, or other cardiovascular causes. The upper 95% confidence limit of the relative risk crossed unity by age 73 years.¹⁰ The findings in 650 patients aged 80 years or older randomized in the Systolic Hypertension in the Elderly Program (SHEP)^16- 17 are in contrast with those of the EWPHE¹⁵ and STOP-Hypertension¹⁰ trials and with the mortality results in the present study (Figure 4). Indeed, in the SHEP trial,^16- 17 the relative risk of stroke on active treatment compared with placebo was 0.51 (95% CI, 0.29-0.89). In view of the remaining uncertainty, the Hypertension in the Very Elderly Trial (HYVET) is currently investigating the potential benefit of antihypertensive drug treatment on stroke and other cardiovascular end points in patients over the age of 80 years.¹⁸ Until the results of this trial are reported, clinicians may consider the possible reduction of nonfatal stroke as the main reason to prescribe antihypertensive agents to very old patients, in whom this complication often undermines precarious autonomy and leads to institutionalization.

In the present analysis, the benefits of active antihypertensive treatment were observed regardless of the blood pressure level at entry. If anything, total mortality declined slightly more on active treatment when the initial systolic blood pressure was higher (Figure 4). Statistical analyses of the EWPHE study¹⁵ and the Medical Research Council¹² trial, which controlled for possible confounders, such as sex, age, and previous cardiovascular complications, did not demonstrate an interaction between the blood pressure level at randomization and the benefit derived from treatment. The SHEP investigators reported that in proportional hazard regression, using systolic blood pressure as a continuous variable, the favorable trend in stroke incidence for the active treatment group compared with the placebo group prevailed irrespective of the baseline systolic blood pressure.^16- 17 The P value for interaction was .13.^17,19 This conclusion was reinforced by similar findings for nonfatal myocardial infarction combined with death from coronary heart disease (P=.85), coronary heart disease (P=.81), and all cardiovascular complications (P=.44).¹⁹ The finding that total mortality in the active treatment group tended to decrease with higher initial systolic blood pressure (Figure 4) is in line with the findings of several reports,^20- 22 which have suggested that pulse pressure behaves as an independent cardiovascular risk factor. Indeed, pulse pressure increases with higher systolic blood pressure and lower diastolic blood pressure and was by definition at least 65 mm Hg in the Syst-Eur patients.

Active treatment in the Syst-Eur trial decreased all strokes by 53% in nonsmokers but did not affect the stroke rate in smokers, who represented less than 8% of the whole trial population. In some studies^12,23- 25 the beneficial effects of β-blockade seemed to be limited to nonsmokers, whereas in other trials the effects were either similar²⁶ in smokers and nonsmokers or tended to be even greater²⁷ in smokers. Several mechanisms have been proposed to explain the apparently lesser reduction of cardiovascular complications by nonselective β-blockade in hypertensive smokers. The catecholamines released by nicotine²⁸ may exert an increased pressor effect when nonselective β-blockers, such as propranolol, inhibit the vasodilating β-receptors, while leaving the vasoconstricting α-receptors unopposed. However, lesser protection in smokers has been found not only with nonselective β-blockers^23- 25 but also with selective β-blockers,¹² with thiazides compared with metoprolol,^27,29 and now in the Syst-Eur trial also with the calcium channel blocker nitrendipine.³ These contradictory findings are likely to reflect random variability or confounding in subgroup analyses. This particularly applies to the Syst-Eur trial, in which the proportion of smokers was very low. Thus, until the contrary is proved in prospective trials with sufficient power, the preventive effects of antihypertensive treatment should be considered to stand regardless of smoking status.

In the EWPHE trial, smoking at randomization was not a significant cardiovascular risk factor.³⁰ In contrast, in the Syst-Eur trial, smoking nearly doubled the risk of total and cardiovascular mortality and combined fatal and nonfatal cardiovascular and cardiac end points (Table 1 and Table 2). In the Medical Research Council trial in young adults with mild hypertension,^23- 24 untreated stroke rates were 2 to 3 times higher in smokers. Similarly, in the Australian Therapeutic Trial in Mild Hypertension (ATTMH),³¹ smoking was associated with raised cardiovascular risk. The trials of antihypertensive drug treatment were not designed to provide direct evidence that stopping smoking would reduce risk but highlight the potential of cardiovascular prevention by persuading patients to stop smoking. Independent data^32- 34 show that the excess risk conferred by smoking is reversible in middle-aged adults. Older people experience the highest rates of cardiovascular disease and therefore theoretically have the best prospect of short-term benefit from smoking cessation. The draft agreement between the attorneys general and the tobacco industry in the United States³⁵ requires the tobacco companies to contribute millions of dollars to campaigns to discourage teenage smoking but does not include specific measures to prove the reversibility of the deleterious effects of smoking on cardiovascular health in the elderly.

Some studies found a positive correlation between alcohol intake and stroke, particularly hemorrhagic stroke.^36- 37 However, prospective studies have demonstrated a U-shaped relationship,^38- 39 with nondrinkers having a higher relative risk of ischemic stroke than moderate drinkers (4-15 g/d), whereas the risk of ischemic stroke increased again in heavy drinkers. In contrast, for hemorrhagic stroke, there was an increased risk at all levels of alcohol intake.³⁹ Nearly 11% of the Syst-Eur patients consumed at least 1 alcoholic beverage per day. However, only 179 subjects (3.8%) consumed more than 20 g/d of alcohol. This probably explains why alcohol intake did not predict outcome in the Syst-Eur trial.

At median follow-up, 14.0% of the Syst-Eur patients who withdrew from active treatment were untreated, whereas among the patients who withdrew from double-blind placebo, 58.1% switched to open-label treatment with antihypertensive drugs.³ For this reason, the analysis by intention to treat was expected to produce lower levels of significance than the per-protocol analysis, which was confined to patients who continued to receive randomized treatment. However, this expectation was entirely fulfilled only for total mortality (Table 3). In general, the intention-to-treat and per-protocol analyses generated remarkably similar results. This may be explained by the fact that, due to the early termination of the trial on February 14, 1997, median follow-up was only 3 months longer, while the analysis also accounted for the end points during open follow-up.

The benefit of antihypertensive treatment is usually expressed in relative terms as the percentage reduction in the event rate compared with the control group. However, this quantity may be misleading, because in absolute terms the number of patient-years of treatment required to prevent one event varies proportionally with the underlying risk as estimated from the event rate observed in the control group.^40- 41 Among 8 intervention trials in the elderly,^8- 13,17 including the Syst-Eur trial (Figure 6), the absolute benefit with regard to all strokes and cardiovascular mortality was small in the group of older patients (≥60 years) enrolled in the ATTMH¹³ and the Medical Research Council trial¹² and large in the STOP-Hypertension trial.¹⁰ The number of strokes or cardiovascular deaths prevented in these trials ranged from 10^12- 13 to 74¹⁰ and from 6^12- 13 to 67¹⁰ per 1000 patients treated for 5 years, respectively. In the analysis by intention to treat, the Syst-Eur results with respect to the number of strokes prevented were in close agreement with those reported by the SHEP trial.¹⁷ In relative terms, the percentage reduction in stroke incidence amounted to 42% and 36%,¹⁷ respectively, while in both trials nearly 30 patients had to be treated for 5 years to prevent 30 strokes. For cardiovascular mortality, the relative benefit in the intention-to-treat analysis amounted to 27% and 20%,¹⁷ respectively, while 5000 patient-years of treatment prevented 18 and 10¹⁷ cardiovascular deaths.

In conclusion, 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, at the rates observed in the placebo group, treating 1000 patients for 5 years may prevent 24 deaths, 54 major cardiovascular end points, 29 strokes, or 25 cardiac end points. The benefit of treatment seemed to be universal, except for total and cardiovascular mortality, which were probably less reduced in very old patients.

Reprints: Jan A. Staessen, MD, PhD, Klinisch Laboratorium Hypertensie, Inwendige Geneeskunde-Cardiologie, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium (e-mail:jan.staessen@med.kuleuven.ac.be).

Accepted for publication January 12, 1998.

The trial was sponsored by Bayer AG, Wuppertal, Germany. The National Fund for Scientific Research, Brussels, Belgium, provided additional support. The study medication was donated by Bayer AG and Merck Sharpe & Dohme Inc, West Point, Pa.

The Syst-Eur trial, initiated by Antoon Amery, MD, who died on November 2, 1994, was a concerted action of the BIOMED Research Program sponsored by the European Union. The trial was carried out in consultation with the World Health Organization, International Society of Hypertension, European Society of Hypertension, and World Hypertension League.

Clinical Investigators

Belgium: Guy Adriaens, MD; Bert Aertgeerts, MD; Clem Agten, MD; Roger André, MD; Jean-Marie Berthot, MD; Guy Beuken, MD; Fernand Bolly, MD; Wim Bos, MD; Etienne Bourdon, MD; Johan Buffels, MD; Erwin Buts, MD; Hilde Celis, MD (Regional Coordinator); Willem Ceyssens, MD; Jean Claus, MD; Denis Clement, MD; Koen Cornelli, MD; Paul De Cort, MD; Eric De Graef, MD; Jean-François De Plaen, MD; Geert Decadt, MD; Eddy Dejaeger, MD; Luc Devriendt, MD; Frank Dewaele, MD; Edward Dierickx, MD; Hervé Dieu, MD; Marc Dobbeleir, MD; Michel Druart, MD; Herman Duprez, MD; Raymond Duyck, MD; Robert Fagard, MD; Frans Francis, MD; Marc Geeraert, MD; Phillippe Gilbert, MD; Michel Glibert-Walgraffe, MD; Jean Gremling, MD; Walter Holsters, MD; Jean-Baptiste Lafontaine, MD; Benoit Langhoor, MD; Vera Leyssens, MD; Filip Libaut, MD; Pierre-Anne Lourtie, MD; Benny Maes, MD; Walter Onsea, MD; Walter Pelemans, MD; Henri Proost, MD; Jean-Paul Rijckaert, MD; Jan A. Staessen, MD; Chris Van Cauwenberge, MD; Hans Vandenabbeele, MD; André Vandenbroeck, MD; Stef Vandervliet, MD; Roger Van Hoof, MD; Jan Van Lint, MD; Daniël Vantroyen, MD; Willy Vanverrewegen, MD; Paul Verhaert, MD; André Vlaeminck, MD.

Belorussia: Irina U. Korobko, MD; Irina V. Lazareva, MD; Maria M. Liventseva, MD; Tatjana A. Nechesova, MD; Georgy I. Sidorenko, MD.

Bulgaria: Rozmari P. Alahverdian, MD; Svesolav G. Andreev, MD; Eugeni D. Anev, MD; Malina N. Antova, MD; Vesselin G. Arabadjiev, MD; Boyan I. Asenov, MD; Valentina Baleva, MD; Anastas Batalov, MD; Sonia B. Beleva, MD; Radka M. Beltcheva, MD; Kolio M. Bianov, MD; Tzetana S Bojanova, MD; Dimitar Z. Bozhinov, MD; Svetla T. Brayanova, MD; Maja P. Dabcheva, MD; Lilia M. Dentcheva, MD; Emil M. Dimitrov, MD; Lilia T. Dimitrova, MD; Todor I. Draganov, MD; Anna Elenkova, MD; Rumiana G. Eremieva, MD; Nicolai B. Ganov, MD; Svetoslav Z. Georgiev, MD; Vesselka I. Gergova, MD; Anton I. Gogov, MD; Eugeni G. Goshev, MD; Mladen Grigorov, MD; Vesselin S. Guidarsky, MD; Iasen G. Ianev, MD; Krassimira Jankulova, MD; Virjinia Jordanova, MD; Deljana K. Kamenova, MD; Rumiana Kermova, MD; Krastjo Kirilov, MD; Lidia Koeva, MD; Zoya Kuneva, MD; Gergana G. Lazarova, MD; Emil Lilov, MD; Eli Lubenova, MD; Stefan I. Mantov, MD; Temenuga Marinova, MD; Rossitsa P. Mateva, MD; Atanes K. Mihov, MD; Lilia Mitkova, MD; Choudomir Nachev, MD (Regional Coordinator); Luba Naidenova, MD; Natalia T. Nikolova, MD; Valeria N. Nikolova, MD; Svetla V. Obretenova, MD; Lilia S. Panteva, MD; Vasa Pasheva, MD; Anton P. Petkov, MD; Peter A. Petrov, MD; Anastas L. Popov, MD; Dimiter G. Popov, MD; Iulia K. Popova, MD; Theodora R. Poryasova, MD; Rada Prokopova, MD; Loida S. Radeva, MD; Rossitsa V. Radoeva, MD; Konstantin N. Ramshev, MD; Katja J. Raykova, MD; Peter B. Rusafov, MD; Boyan E. Shahov, MD (deceased); Zdravka Simeonova, MD; Vera Sirakova, MD; Albena T. Slavtcheva, MD; Diana S. Smilcova, MD; Panajot Solakov, MD; Anna Spasova, MD; Margarita Staneva, MD; Zlatinca M. Stereva, MD; Vassil Stoyanovsky, MD; Tsevtan Tchernev, MD; Snejana Tisheva, MD; Katja T. Todorova, MD; Maya Todorova, MD; Maria Tzekova, MD; Ivan N. Tzenov, MD; Vassel H. Vasilev, MD; Todorka N. Vasileva, MD; Ventrislav I. Veselinov, MD; Angel Volcov, MD; Kiril Yablanski, MD; Yoto T. Yotov, MD; Masusia A. Zaprianova, MD; Rozisa Zdravcova, MD; Zachezar Zozanov, MD.

Croatia: Nediljko Pivac, MD; Zvonko Rumboldt, MD.

Estonia: Tovio Laks, MD; Toomas Podar, MD; Ulle Planken, MD.

Finland: Jari Airas, MD; Maija Alaluoto, MD; Riitta Antikainen, MD; Mikko V. Haapio, MD; Tapio Hakamäki, MD; Kari Halonen, MD; Matti Jääskivi, MD; Seppo Y. Junnila, MD; Ekki Karonen, MD; Paula Kivinen, MD; Paula S. Kohonen-Jalonen, MD; Pasi Kuusisto, MD; Aapo Lathonen, MD; Anneli Latva-Nevala, MD; Eero Lehmus, MD; Erkki Lehtomäki, MD; Raimo Puustinen, MD; Rita Ristolainen, MD; Eeva Ruotsalainen, MD; Cinzia Sarti, MD; Reijo Tilvis, MD; Jaakko Tuomilehto, MD (Regional Coordinator); Hannu Vanhanen, MD (Associate Member of the End Point Committee); Olavi Vänskä, MD; Hilkka Viitanen, MD; Mirjami Viitaniemi, MD; Seija Vinni, MD; Hannu Wallinheimo, MD.

France: Philippe Archaud, MD; Jean-Marc Aupy, MD; Georges Baudassé, MD; Pierre Berger, MD; Antoine Berthelot, MD; Françis Bezot, MD; Benoît Bombecke, MD; Loic Boucher, MD; Jérôme Bousac, MD; Alain Boye, MD; Alain Campagne, MD; Jackie Castellani, MD; François Coisne, MD; Christian Copere, MD; Jean-Achille Cozic, MD; Eric De Sainte Lorette, MD; Alain Delelis-Fanien, MD; Bernard Diadema, MD; Gérard Donnarel, MD; Michèle Escande, MD; Gilles Etchegaray, MD; Hervé Feuillette, MD; Yves-Michel Flores, MD; Françoise Forette, MD (Regional Coordinator); François Fouquet, MD; Gilles François, MD; Isabelle Gabilly, MD; Christian Gaillard, MD; Armelle Gentric, MD; Xavier Girerd, MD; Robert Gorlier, MD (deceased); Alexis Gracovetsky, MD; Michel Grégoire, MD; Ghislaine Henry, MD; Guy Herry, MD; Suzanne Houdry-Pavie, MD; Jean-Richard Israel, MD; Jean-Pierre Jacquemart, MD; Paul-Louis Jacquier, MD; Bruno La Salle, MD; Florence Latour, MD; Jean-Bernard Leblond, MD; Jean-Luc Lebrun, MD; Michel Masieri, MD; Gilles Merceay, MD; Charles-Henri Mercier, MD; Gilbert Meridjen, MD; Pierre Mours, MD; Alain Neveur, MD; Isabelle Périlliat, MD; Dominique Pineau-Valancienne, MD; Alain Pistre, MD; Louis-Marie Pommier, MD; André Ponsot, MD; Jean Pontonnier, MD; Hugues Pujade, MD; Elisabeth Quignard, MD; Didier Rabaud, MD; François Regnaut, MD; Jean-Pierre Ribat, MD; Joël Richard, MD; Claude Robin, MD; Philippe Romejko, MD; Michel Safard, MD; Raymond-Philippe Sarfati, MD; Alain Sarradon, MD; Nicole Savary, MD; Marie-Laure Seux, MD; Marie-Annick Terrienne, MD; Jean-Marc Vigne, MD; Marc Zecconi, MD; Georges Zerbé, MD.

Germany: Jutta Enderlein, MD; Hans-Dieter Faulhaber, MD; Claudia Heuel, MD; Stephan Matthias, MD; Eberhard Ritz, MD (Regional Coordinator); Gisela Schundau, MD; Uwe Zwettler, MD.

Greece: Aris D. Efstratopoulos, MD; Kyprionos Nikolaides, MD.

Ireland: Liza Bradley, MD; Danny Collins, MD; John Cox, MD; Joe Duggan, MD; Peter Dupont, MD; Doreen Fagan, MD; Pamela Lennox, MD; Brian Lucey, MD; Fáinsía Mee, RN; Catherine McElearny, MD; Eoin T. O'Brien, MD (Regional Coordinator); Kevin O'Malley, MD; Niall Power, MD; Rònan Ryan, MD; Michael Scully, MD.

Israel: Geoffrey Boner, MD; Custava Bott-Kanner, MD; Jose Fidel, MD; Adiv Goldhaber, MD; Eldad Kisch, MD; Irene Kruchin, MD; Alon Margalit, MD; Ilana Moran, MD; Gina Moshe, MD; Joseph Rosenfeld, MD (Regional Coordinator); Naftali Stern, MD; Chave Tabenkin, MD; Jack R. Viskoper, MD; Sarah Yodfat, MD; Yair Yodfat, MD; Chaim Yosephy, MD; Jose Zabludowski, MD; Serge Zerapha, MD.

Italy: Basem Abotel-Hag, MD; Ernesto Agostinacchio, MD; Aldrovandi Alessandro, MD; Michele Amoruso, MD; Francesco Bartolomucci, MD; Gratia Bergognoni, MD; Alfredo Bossini, MD; Vito Cagli, MD; Alberto Capra, MD; Mario Condorelli, MD; Mariarosa Del Torre, MD; Rosa Di Mise, MD; Claudio Diveroli, MD; Ernesta Dolce, MD; Monica Fastidio, MD; Roberto Fogari, MD; Evangelo Ivan, MD; Sattuada Lattuada, MD; Gastone Leonetti, MD (Regional Coordinator); Almado Libretti, MD; Fabio Lissoni, MD; Giuseppe Maiorano, MD; Giandomenico Malamani, MD; Massimo Merlo, MD; Francesco Minenna, MD; Pietro Nazarro, MD; Angela Palasciano, MD; Paolo Palatini, MD; Carlo Pasotti, MD; Riccardo Pieri, MD; Nazzaro Pietro, MD; Anna Pirrelli, MD; Alessandro Rappelli, MD; Elisabetta Roman, MD; Antonio Salvetti, MD; Michela Simi, MD; Laura Terzoli, MD; Franco Tettamanti, MD; Bruno Trimarco, MD; Alvaro Vaccarella, MD; Vito Vulpis, MD.

Lithuania: Marija R. Babarskiene, MD; Abromiskes Bickauskaite, MD; Jolanta Jasilionyte, MD; Juozas Paukstys, MD; Daiva Rastenyte, MD; Aldona Sereniene, MD.

The Netherlands: Willem H. Birkenhäger, MD (Regional Coordinator); Peter W. de Leeuw, MD; Willibrord H. L. Hoefnagels, MD; Arie T. J. Lavrijssen, MD; Arie H. Van den Meiracker, MD; Norbert F. Vogel, MD; Pieter H. Wassenberg, MD; Anton B. Wermenbol, MD; Anno Wester, MD; Arend J. Woittiez, MD.

Poland: Jacek Baszak, MD; Leszek Bieniaszewski, MD; Barbara Broniarczyk, MD; Danuta Czarnecka, MD; Urszula Czubeck, MD; Tomasz Grodzicki, MD; Barbara Gryglewska, MD; Urszula Iwicka, MD; Anna Jach, MD; Kalina Kawecka-Jaszcz, MD; Mariusz Kazmirowicz, MD; Marek Klocek, MD; Jozef Kocemba, MD (Regional Coordinator); Barbara Krupa-Wojciechowska, MD; Marian Markiewicz, MD; Danuta Mroczek-Czernecka, MD; Edmund Nartowicz, MD; Wieslawa Piwowarska, MD; Krystyna Rachon, MD; Marek Rajzer, MD; Michal Tendera, MD.

Portugal: Rosa Afonso, MD; Teleforo B. Afonso, MD; Anabela Bitoque, MD; Anibal Caetano, MD; Almada Cardoso, MD; Manuel Carrageta, MD (Regional Coordinator); Helena Concalves, MD; Ana Costa, MD; Diniz Deolinda, MD; José Domingues, MD; Afredo Franco, MD; Gago Leiria, MD; Assuncao Martinez, MD; Armando Medeiros, MD; A. Moeda, MD; Ana Nunes, MD; Pedro Nunes, MD; Rogerio Nunes, MD; José Pascoal, MD; Salome Pereira, MD; Neves Rodrigues, MD; Gaime Segal, MD.

Romania: Speranta Babeanu, MD; Violeta Bogdaneanu, MD; State Doina, MD; Rozeta Draghici, MD; Diana Dumitrascu, MD; Dan L. Dumitrascu, MD; Lavinia Serban, MD.

Russian Federation: Olga Akimora, MD; Guramy G. Arabidze, MD (Regional Coordinator); Yuri B. Belousov, MD; Robert S. Bogachov, MD; Lada V. Budrina, MD; Tatjana A. Chlyabi, MD; Angela V. Demenova, MD; Olga V. Efremenkova, MD; Angelina E. Ershova, MD; Alla Y. Ivleva, MD; Tolyana B. Kasatova, MD; Victoriya Kirilyuk, MD; Janna D. Kobalava, MD; Irina A. Komisarenko, MD; Irina V. Kondratova, MD; Irina L. Konstantinova, MD; Alexander Kopelev, MD; Oleg A. Kozyrev, MD; Leonid B. Lazebnik, MD; Marina V. Leonova, MD; Veronika V. Lopykhova, MD; Irina P. Malaya, MD; Natalya V. Malysheva, MD; Olga M. Milyukova, MD; Sergey Moisseyev, MD; Valentin Moisseyev, MD; Sergey V. Nedogoda, MD; Taras M. Nesterenko, MD; Elena V. Oshchepkova, MD; Ludmila E. Salisheva, MD; Tatjana N. Sanina, MD; Inna M. Semenova, MD; Elena Senik, MD; Ekaterina Shkolnikova, MD; Madina M. Sidakova, MD; Boris A. Sidorenko, MD; Aleksei K. Starodoubtsev, MD; Gennady I. Storozhakov, MD; Marina V. Taranova, MD; Sergey Tereshchtenko, MD; Elena A. Toporova, MD; Galina A. Vereshchagina, MD; Sergey K. Zubkov, MD.

Slovakia: Zora Gérová, MD; Katha Jureckova, MD; Katha Sedlakova, MD.

Slovenia: Rok Accetto, MD; Bruno Bucic, MD; Jurij Dobovisek, MD; Primoz Dolenc, MD; Borut Kolsek, MD; Zdenko Lapanja, MD; Maja Mihelic-Brcic, MD; Jurij Petrin, MD; Olga Pirc-Cercek, MD; Ales Zemva, MD.

Spain: José Abellan, MD; Javier Aranda, MD; Manuel Arjona-Garcia, MD; Maria Barreda, MD; Gador Chamorro-Barrionuevo, MD; José Fernandez, MD; Blas Gill-Extremera, MD; Luis Gonzalez-Gomez, MD; Pedro Aranda-Lara, MD; Antonia Maldonado-Martin, MD; Rafael Marin, MD; Josefina O. Martinez, MD; Fernando H. Meneguez, MD; Rex Molina, MD; José Mora-Macia, MD; Ernesto Lopez de Novales, MD; Joan Ocón-Pujadas, MD; José Ortega, MD; Alenta H. Pardell, MD; Fernanda Plaza, MD; Josep Redón, MD; José L. Rodicio, MD (Regional Coordinator); Luis M. Ruilope, MD; Leticia Soriano-Carrascosa, MD; Francisco F. Vega, MD.

United Kingdom: Peter Andrews, MD; Sally G. Armstrong, RN; Gareth D. Beevers, MD; Michèle Beevers, MD; P. Bruce-Jones, MD; Christopher J. Bulpitt, MD (Regional Coordinator); David Choat, MD; Wendy Crichton, RN; Peter Crome, MD; Christopher Davidson, MD; Colin T. Dollery, MD; Astrid E. Fletcher, PhD; Nicola Gainsborough, MD; Nandin D. P. Gunawardena, MD; Nigel Higson, MD; Stephen Jackson, MD; Christopher Kingswood, MD; David Kluth, MD; Dan Lee, MD; Peter J. Luce, MD; Ganesh Mankikar, MD; Anthony O'Brien, MD; Hugh O'Neal, MD; James C. Petrie, MD; Chakravarthi Rajkumar, MD; Andrew K. Scott, MD; Paul Sharpstone, MD; David I. Slovick, MD; Ian D. Starke, MD; Jean Timeyin, RN; Kenneth Tsang, MD; John Webster, MD; Peter Wilkinson, MD; Katia Witte, RN.

Committees and Coordination

Trial Coordinators: Robert Fagard, MD; Jan A. Staessen, MD.

Data Monitoring Committee: Christopher J. Bulpitt, MD; Astrid E. Fletcher, PhD; Jan A. Staessen, MD; Lut Thijs, BSc.

Drug Committee: Hilde Celis, MD; Guy Demol, MD; Pierre Demol, MD; Robert Fagard, MD; Günther E. Hübner, MD; Jan A. Staessen, MD.

End Point Committee: Peter W. de Leeuw, MD; Robert Fagard, MD; Gastone Leonetti, MD; James C. Petrie, MD.

Ethics Committee: Willem H. Birkenhäger, MD; Colin T. Dollery, MD; Robert Fagard, MD.

Liaison Committee With the European Union: Willem H. Birkenhäger, MD; Fernando De Padua, MD; Colin T. Dollery, MD; Aris D. Efstratopoulos, MD; Robert Fagard, MD; Françoise Forette, MD; Detlev Ganten, MD; Eoin T. O'Brien, MD; Kevin O'Malley, MD; José L. Rodicio, MD; Jaakko Tuomilehto, MD; Charles van Ypersele, MD; Alberto Zanchetti, MD.

Publication Committee: Willem H. Birkenhäger, MD; Christopher J. Bulpitt, MD; Jan A. Staessen, MD; Alberto Zanchetti, MD.

Steering Committee: Guramy G. Arabidze, MD; Paul De Cort, MD; Robert Fagard, MD; Françoise Forette, MD; Kalina Kawecka-Jaszcz, MD; Gastone Leonetti, MD; Choudomir Nachev, MD; Eoin T. O'Brien, MD; José L. Rodico, MD; Joseph Rosenfeld, MD; Jaakko Tuomilehto, MD; John Webster, MD; Yair Yodfat, MD.

Coordinators of the Project on Ambulatory Blood Pressure Monitoring: Denis Clement, MD; Eoin T. O'Brien, MD; Giuseppe Mancia, MD; Gianfranco Parati, MD; Jan A. Staessen, MD; Lut Thijs, BSc.

Coordinators of the Project on Vascular Dementia: Françoise Forette, MD; Thomas Strasser, MD.

Coordinators of the Project on Quality of Life: Christopher J. Bulpitt, MD; Astrid E. Fletcher, PhD.

Coordinators of General Practices: Hilde Celis, MD, in collaboration with Jan Heyrman, MD; Gérard Stibbe, MD; Michel Van den Haute, MD; Yair Yodfat, MD.

Coordinating Office: Nicole Ausseloos; Hilde Celis, MD; Lut De Pauw RN; Paul Drent; Dimitri Emelianov, MD; Robert Fagard, MD; Heng Fan; Tatjana Kutznetsova, MD; Viviane Mariën; Yvette Piccart; Jan A. Staessen, MD; Yvette Toremans; Lut Thijs, BSc; Sven Vandenreycken; Roger Van Hoof, MD; Sylvia Van Hulle, RN; Jiguang Wang, MD (liaison with the Syst-China Trial Investigators); Renilde Wolfs.

Regional Drug Dispatching Centers: Mariana Bontscheva, MD (Bulgaria); Carola Borsati, MD (Germany); Lesly Carmody, MD (United Kingdom); Efrat Caspi, MD; Daniel Koerner, MD (Israel); Sabine Coppens, MD (Belgium); Hans Eeltink, MD (the Netherlands); Mariangela Ferrari, MD (Italy); Konsantin Gravilov, MD (Belorussia and the Russian Federation); Janko Hacundova, MD (Slovakia); Maija Kinnunen, MD (Estonia, Finland, and Lithuania); Nada Lozey, MD (Slovenia); Antonio Nolasco, MD (Portugal); Janina Pawlowska, MD (Poland); Marc Pételaud, MD (France); Carmen Pinol, MD (Spain); George Sotiriadis, MD (Greece); Marija Stipic, MD (Croatia); Maya Thompson, MD (Ireland); Doina Verzea, MD (Romania); Jaroslava Vylitova, MD (Czech Republic).