Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators.

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.

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

BACKGROUND: Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebo-controlled 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 (DSM-III-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 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.

Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project.

OBJECTIVE: To assess cognitive functions and their correlates for a dementia-free cohort of old patients with isolated systolic hypertension. DESIGN: Cross-sectional data from the randomization period of the European Trial in Elderly with Systolic Hypertension (Syst-Eur Vascular Dementia Project). SETTING: Sixteen European countries and Israel. PARTICIPANTS: We studied 2252 patients aged 60-100 years (mean 70). MAIN OUTCOME MEASURES: Mini Mental State Examination (MMSE) and Spearman correlation of MMSE scores to demographic data or blood pressure. RESULTS: The MMSE was successfully completed for 1474 women and 751 men. The baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg (means +/- SD). Median age at which education of patients at school had stopped was 15 years. Men and women who consumed alcohol (28%) had median intakes of 8 and 3 g/day, respectively. The median MMSE score was 29 (range 15-30). The maximum score of 30 was attained by 609 (30%) subjects. Fifty-nine (3%) patients had a MMSE score of 23 or less. The MMSE score decreased with advancing age (r = -0.21, P < 0.001). Both for men and for women, it was positively correlated to the level of education (r = 0.30 and r = 0.32, P < 0.001). For women after adjustment for age and the level of education, the score was correlated negatively to systolic blood pressure (r = -0.07, P < 0.05) but positively to intake of alcohol (r = 0.06, P < 0.05). CONCLUSION: In a cohort of elderly patients with isolated systolic hypertension, baseline cognitive function measured in terms of the MMSE score was high, probably due to selective recruitment of patients who were not clinically demented. Blood pressure was a weak contributor to cognitive status compared with age and level of education. Baseline cognitive function of women was negatively and independently correlated to systolic blood pressure.

Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension.

In the double-blind Systolic Hypertension in Europe (Syst-Eur) Trial, active treatment was initiated with nitrendipine (10 to 40 mg/d) with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d) titrated or combined to reduce sitting systolic blood pressure by at least 20 mm Hg to <150 mm Hg. In the control group, matching placebos were used similarly. In view of persistent concerns about the use of calcium channel blockers as first-line antihypertensive drugs, this report explored to what extent nitrendipine, administered alone, prevented cardiovascular complications. Age at randomization averaged 70.2 years and systolic/diastolic blood pressure 173.8/85.5 mm Hg. Of 2398 actively treated patients, 1327 took only nitrendipine (average dose, 23.4 mg/d), and 1042 progressed to other treatments including nitrendipine (n=757; 35.7 mg/d), enalapril (n=783; 13.4 mg/d), and/or hydrochlorothiazide (n=294; 21.0 mg/d). Compared with the whole placebo group (n=2297), patients receiving monotherapy with nitrendipine had 25% (P=0.05) fewer cardiovascular end points, and those progressing to other active treatments showed decreases (P

Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly.

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 perprotocol 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.

Therapy in old patients with isolated systolic hypertension: fourth progress report on the Syst-Eur trial.

The Syst-Eur trial is a multicentre, randomized, double-blind, placebo controlled therapeutical trial in patients at least 60 years old and with isolated systolic hypertension. Its scope is to investigate the effects of modern antihypertensive drug treatment on morbidity and mortality and to assess possible adverse effects of the drugs used. Patients were recruited in 22 countries in western and eastern Europe and Israel. At three run-in visits 1 month apart their sitting systolic blood pressure (SBP) on single-blind placebo treatment averaged 180-219 mm Hg with diastolic blood pressure (DBP) lower than 95 mm Hg. After stratification for sex and the presence of cardiovascular complications, the patients were randomized either to active treatment or placebo. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day) and/or hydrochlorothiazide (12.5-25 mg/day), titrated or combined to reduce the sitting SBP by at least 20 mm Hg to below 150 mm Hg. Matching placebos were employed similarly. The present progress report is based on the data received at the Coordinating Office before 1 March 1996. At that time 3433 subjects had been randomized. A total of 2015 patients had been followed for at least 1 year on double-blind treatment and 1298 patients for at least 2 years. At baseline BP was similar in both treatment groups and averaged 174/86 mm Hg. According to a per-protocol analysis at 1 year, BP fell (P < 0.001) on average by 22.6 +/- 15.7/6.0 +/- 8.0 mm Hg in the active treatment group and by 12.2 +/- 15.9/1.7 +/- 7.3 mm Hg in the placebo group. At 2 years BP was 10.2/5.7 mm Hg lower (P < 0.001) on active treatment than on placebo. At 1 year the percentage of patients who had reached goal BP was 19.9% in the placebo group and 41.4% in the active treatment group. At 2 years these percentages were 20.9 and 43.2 respectively.

Antihypertensive therapy in older patients with isolated systolic hypertension: the Syst-Eur experience in general practice. The Syst-Eur Investigators.

BACKGROUND AND OBJECTIVE: This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practices. METHODS: In the Syst-Eur trial elderly patients (60 years or older) with isolated systolic hypertension were randomized to either active or placebo treatment. Active treatment consisted of nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce systolic pressure to < 150 mmHg and by > or = 20 mmHg. Matching placebos were used in the control group. RESULTS: This analysis was restricted to patients of general practitioners who had been followed for at least 12 months. The placebo (N = 204) and active treatment (N = 217) groups had similar characteristics at randomization. At one year, the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier. Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment (P < 0.001 for all comparisons). CONCLUSIONS: A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners. Whether this blood pressure reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation.

Quality of life in normotensives compared to hypertensive men treated with isradipine or methyldopa as monotherapy or in combination with captopril: the LOMIR-MCT-IL study.

Quality of life (QOL) measures were assessed in a multi-center, double-blind, case-controlled trial of 1 year's duration. A total of 368 hypertensive male patients were randomly assigned to monotherapies of either isradipine, methyldopa or placebo. If normotension was not achieved, captopril was added. QOL assessments in the hypertensives and in 155 normotensives included a self-structured scale to measure the subjective perception of QOL, the severity, desirability and controllability of recent critical life events, semantic memory, physical dysfunction, sleep disorders, sexual difficulties, depression and work-related stress. The overall withdrawal rate during the trial was 19%, mainly due to lack of efficacy and adverse experiences. At baseline, and at the end of the trial, the normotensives as compared to hypertensive patients, had significantly better scores in most QOL measures. Patients treated with the combination of isradipine and captopril reported more favorable changes in the subjective measure of QOL (P < 0.03) and in semantic memory (P < 0.001) than patients treated with any of the monotherapies or with methyldopa in combination with captopril. There were no statistically significant differences among treatments for changes of other indices of QOL. In most QOL measurements, normotensives rated better then hypertensives. Patients treated on long-term therapy with the combination of isradipine and captopril showed improvement in self-structured QOL measures and semantic memory, compared to patients treated either with methyldopa or placebo.

Antihypertensive therapy in older patients with isolated systolic hypertension: the Syst-Eur experience in general practice

Background and objective. This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practices. Methods. In the Syst-Eur trial elderly patients (60 years or older) with isolated systolic hypertension were randomized to either active or placebo treatment. Active treatment consisted of nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce systolic pressure to Results. This analysis was restricted to patients of general practitioners who had been followed for at least 12 months. The placebo (N = 204) and active treatment (N = 217) groups had similar characteristics at randomization. At one year, the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier. Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment (P Conclusions. A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners. Whether this blood pressure reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation. Keywords. Antihypertensive treatment, general practice, isolated systolic hypertension, randomized clinical trial.

[A multicenter study of lisinopril in the treatment of mild to moderate hypertension].

The efficacy, tolerability and impact on quality of life of the ACE inhibitor lisinopril were evaluated in a 12-week open, multicenter post-marketing surveillance study. 233 patients, 45 years and over with diastolic blood pressure (DBP) 95-105 mm Hg were followed after a washout period of 7 days. 22 withdrew due either to adverse reactions, mainly cough (4.3%) and dizziness (3%), or noncompliance. DBP of 90 mm Hg or less was achieved in 50.7% with once-a-day 10 mg lisinopril, in 26.1% with 20 mg and in 16.1% with 20 mg plus addition of hydrochlorothiazide, 12.5 mg; in only 7.1% was BP not controlled. Adverse reactions other than cough or dizziness were experienced by fewer than 1%. Dartmouth COOP Functional Health Assessment Charts/WONCA were used to evaluate quality of life and were found useful in the study. Compared to baseline assessments, all functional status indicators (physical fitness, feelings, daily activities, social activities, change in health and overall health) scored significantly better in all treated patients after 12 weeks. Thus, in more than 90% of patients lisinopril was well-tolerated, highly effective in lowering blood pressure and possibly (no control group) improved the quality of life of all patients.

Impact of comorbidity on well-being in hypertension: case control study.

The impact of hypertension and comorbidity on reporting of well-being was compared in hypertensives (n = 45) and normotensives (n = 45) matched for age, sex and ethnic origin. Self-reported health, measured by the Duke profile, was worse for most measures for the hypertensive group. The mean DUSIO (Duke Severity of Illness Scale) severity of illness score, the physicians' assessment of the subject's health, was significantly higher in hypertensives than in normotensives (40.8 vs. 29.1, P = 0.04). Approximately 20% of the variance in well-being scores could be explained by comorbidity. Hypertension per se explained only 2% of the variance and its correlation with well-being was not statistically significant. Perception of health (a subscale of the DUKE) was somewhat more dependent on existence of hypertension. In this study, self-assessment of health and well-being are explained to a large extent by differences in comorbid conditions. Well-being is independent of hypertension. These findings underscore the importance of defining and ameliorating co-existing disease in patients with hypertension.

Effect of patient characteristics and disease manifestations on the outcome of acute otitis media at 2 months.

BACKGROUND: Optimal therapy for acute otitis media (AOM) is controversial and there is no consensus regarding which antibiotic to use, how long to administer it, or whether antibiotics are effective at all. Knowledge of the effects of patient characteristics and disease manifestations is needed to individualize treatment and to evaluate large-scale trials. METHODS: Data originated from 2251 patients with AOM, aged newborn to 15 years, who participated in a prospective primary care study in eight countries. At the initial visit, medical history, symptoms, physical findings, and treatment data were recorded. Follow-up 2 months later identified changes in treatment and outcome. RESULTS: Patients younger than 13 months were less likely to have recovered than those aged 13 months to 15 years (P = .05). Using univariate analysis for infants aged 12 months or younger, male sex, prior episodes of AOM, and serous otitis media were associated with poor outcome. For older patients, poor outcome was associated with initial history of ear tubes, prophylactic antibiotic use, ear discharge, decreased hearing, serous otitis media; and past episodes of AOM; the symptom of decreased hearing; and the finding of pus exuding from the tympanic membrane. Using multivariate analysis for infants aged 12 months or younger, a history of serous otitis media (odds ratio [OR], 2.3; 95% confidence interval [CI], 0.95-5.7), past episodes of AOM (OR, 1.9; 95% CI, 0.82-4.5), and male sex (OR, 1.7; 95% CI, 1.0-3.0) made independent contributions to poor outcome. For children aged 13 months to 15 years, significant variables included pus drainage (OR, 2.2; 95% CI, 1.5-3.3), a history of ear tubes (OR, 2.3; 95% CI, 1.5-3.6), past episodes of AOM (OR, 1.8; 95% CI, 1.3-2.34), and a history of serous otitis media (OR, 1.4; 95% CI, 1.0-1.9). CONCLUSIONS: Patient characteristics and disease manifestations are significant determinants of AOM outcome.

A multicenter, double-blind, randomized, placebo-controlled study of isradipine and methyldopa as monotherapy or in combination with captopril in the treatment of hypertension. The LOMIR-MCT-IH Research Group.

This multicenter, double-blind, randomized trial of 1 year's duration compared the safety and efficacy of isradipine, methyldopa, and placebo in 368 men, aged 40 to 65 years, with mild-to-moderate essential hypertension. Initial treatment with isradipine (1.25 mg twice daily), methyldopa (250 mg twice daily), or placebo was started after a wash-out and single-blind placebo period. If normotension [diastolic blood pressure (DBP) < 95 mm Hg] was not achieved, doses were doubled. If the maximum dose as monotherapy did not result in normotension, captopril (25 mg or, if necessary, 50 mg, once daily) was added to the treatments of the three patient groups. Despite the marked placebo effect during the first 2 weeks of treatment, monotherapy with isradipine resulted in a higher rate of normalization (more than 64%) compared with 50% in the methyldopa group and 36% in the placebo group. Adding captopril to the treatments of non-responders increased the rate of normalization to 90% in the isradipine group, 84% in the methyldopa group, and 75% in the placebo group. Twenty-one patients dropped-out and 70 patients discontinued the study, the majority because of a lack of efficacy and adverse reactions. The most common adverse reactions reported were cardiovascular and gastrointestinal complaints, headaches, and sleep and sexual disorders, mostly by patients taking methyldopa. Isradipine was well tolerated and the side-effects were minimal. These results indicate that isradipine is superior to methyldopa and, whether as monotherapy or in combination with captopril, highly effective and well tolerated in the treatment of mild-to-moderate hypertension.

Psychosocial stress and NK cells among members of a communal settlement.

The aim of the present study was to assess the effect of daily psychosocial stress on the human immune system. We tested 38 couples living in a communal settlement (kibbutz) under similar economic and social conditions, sharing similar housing, nutrition and health care. They were tested repeatedly over a two year period for a number of psychosocial parameters including demoralization, social support, family cohesion, adaptational hardiness and hostility. In parallel, the natural killer "NK" cell system was analysed for distinctive markers and for cytotoxic activity. The proportion of CD16+ lymphocytes was found to correlate with cytotoxic NK activity in both men and women. In contrast, the proportion of CD57+ cells correlated with that of CD16+ cells only in women while in men only the CD57+CD8-lymphocytes subset correlated with CD16+ cells. For each individual tested, the values of NK activity and NK markers obtained in tests carried out more than a year apart showed a striking correlation. In males, NK cytotoxicity correlated with hostility but was negatively correlated with family cohesion, adaptability and hardiness. The level of CD16+ and CD57+ cells correlated positively with demoralization in males only. Changes in the level of NK activity and in the level of CD16+ cells occurring in husbands during the observation period correlated positively with changes in demoralization and negatively with changes in family cohesion and adaptability. The results indicate that daily psychological stress and low family function may enhance the NK system, and that this response may differ between the sexes.

[Anemia in Jerusalem children aged 3-6 years].

Anemia in Israel is prevalent in nursing infants but there are few data on its prevalence in children aged 3-6 years. In 436 children in this age group in 18 family practice clinics in the Jerusalem area a hemoglobin level of less than 11.0 g% was found in only 17 (3.9%). Age, sex, and suburban versus urban residence were not related to the incidence of anemia. In 74 children (17%) the average mean red cell volume (MCV) was less than 74 fl but it was not associated with low hemoglobin. This finding might indicate the presence of thalassemia or a predisposition to the development of iron deficiency. This group of children is at risk of developing iron deficiency anemia and therefore requires follow-up. Results of blood tests at ages 9-12 months were available in 198 of the children but the results were not of high predictive value for the development of iron deficiency at 3-6 years of age. Iron supplementation administered to them when nursing did not affect the incidence of anemia in the children studied.

[Sustained release verapamil in essential hypertension].

The efficacy of sustained release verapamil (Ikapress) was investigated in 237 hypertensive patients of both sexes in a multicenter trial in family practice. There were 4 groups: patients without previous treatment and those treated with nifedipine, with atenolol, or with a combination of drugs. After 4-7 days of washout, all those with diastolic pressures of 95 mm Hg or above received once daily 240 mg of verapamil for 8 weeks. 27 cases had to be withdrawn because of adverse effects: weakness in 10, constipation in 6, rash in 4, impotence in 3, and in 4, other reasons. In 177 blood pressure was brought under control after 4 weeks of treatment. An additional 33 were controlled after 4 weeks of 360 mg of sustained release verapamil. Response to treatment was similar in the 4 trial groups. Mean systolic and diastolic pressures fell 19 and 16 mm Hg, respectively, and mean pulse rate decreased by 5 beats/min. Constipation was the only side-effect reported by those who completed the trial. However, there was a significant reduction in initial scores for headache, dizziness, numbness and edema after 8 weeks of verapamil and all indices of quality of life were significantly improved. These included scores for general well-being, physical fitness, social activity, job fitness, sexual activity, sleep, concentration and mood. Scores for daytime sleepiness and fatigue also decreased significantly. Thus, sustained-release verapamil in a daily dose of 240-360 mg was shown to be an effective antihypertensive. It had few adverse effects and gave considerable improvement in quality of life.