H Vanhanen

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

BACKGROUNDnSystolic 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.nnnMETHODSnEligible 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.nnnFINDINGSnMedian 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).nnnINTERPRETATIONnIn 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.

Response to Antihypertensive Therapy in Older Patients With Sustained and Nonsustained Systolic Hypertension

BackgroundThe goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. Methods and ResultsPatients who were ≥60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (≥160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P <0.001) and, during follow-up, a lower incidence of stroke (P <0.05) and of cardiovascular complications (P =0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P <0.001). The influence of active treatment on ECG voltages (P <0.05) and on the incidence of stroke (P <0.05) and cardiovascular events (P =0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. ConclusionsPatients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.

Ambulatory Monitoring Uncorrected for Placebo Overestimates Long-term Antihypertensive Action

This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (> or = 60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of 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). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (P<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (P<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (P<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration.

Quality of life of elderly patients with isolated systolic hypertension: baseline data from the Syst-Eur Trial

Objective To describe measures of quality of life of elderly patients with isolated systolic hypertension at entry to a placebo-controlled randomized trial of antihypertensive treatment and to investigate factors associated with these. Design Cross-sectional analyses at entry to a randomized controlled trial. Setting Patients attending hypertension clinics or general practitioners surgeries at 30 centres in 10 European countries. Patients Six hundred and thirty-one patients aged 60 years or more, with a sitting systolic blood pressure during the run-in phase of 160–219 mmHg, a sitting diastolic blood pressure below 95 mmHg and a standing systolic blood pressure of 140 mmHg or more. Main outcome measures Cognitive function tests (Reitan Trail Making A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest and Housework). Results Poor quality of life was generally associated with increasing age, previous treatment with antihypertensive drugs, presence of cardiovascular complications and, among women, high diastolic blood pressure, higher consumption of alcohol and high body mass index. Conclusions At entry to the trial there was considerable heterogeneity of patients in terms of measures of quality of life and cognitive performance. It remains to be determined whether these influence subsequent quality of life during randomized treatment.

Associations of orthostatic blood pressure fall in older patients with isolated systolic hypertension

Objectives To investigate the associations of the orthostatic blood pressure changes in older patients with isolated systolic hypertension. Methods A total of 2716 patients, 917 men and 1799 women, aged ≥60 years, were examined at three separate outpatient visits whilst receiving placebo during the single-blind run-in phase of the Syst-Eur trial. The orthostatic blood pressure changes were calculated by subtracting the average of two blood pressure readings with the patient in the supine position from the mean of two readings obtained after the patient had stood for 2 min. An orthostatic blood pressure drop by at least 20mmHg systolic or 10mmHg diastolic was considered exaggerated. Results For the three run-in visits combined, the supine blood pressure was 175 ± 13 mmHg systolic and 86 ± 6 mmHg diastolic (means ± SD). With the patients standing the systolic blood pressure was 5 ± 12 mmHg lower, whereas the diastolic blood pressure was 2 ± 7 mmHg higher. An exaggerated fall in systolic blood pressure was observed on at least 1 visit in 21.0% of the patients and on all three visits in 2.5%. The corresponding values for diastolic blood pressure were 9.7 and 0.4%. The orthostatic fall in systolic blood pressure increased with previous antihypertensive treatment, age and smoking, but decreased with a higher sitting pulse rate and usual alcohol consumption versus none. The rise in diastolic blood pressure upon standing was higher in women than in men, was curvilinearly associated with age and increased with the sitting diastolic blood pressure. By multiple logistic regression analysis, the odds of having a persistent or occasional exaggerated orthostatic fall in systolic blood pressure were 22% higher in women than in men. The odds increased with previous antihypertensive treatment (by 42%), age (by 1.4%/year), electrocardiographic left ventricular mass (by 15%/mV) and sitting systolic blood pressure (by 0.9%/mmHg), but decreased with sitting pulse rate (by 1.9%/beat per min). An exaggerated orthostatic fall in diastolic blood pressure was 30% more likely in men; the likelihood increased with age (by 6.4%/year) and decreased with sitting diastolic blood pressure (by 6.6%/ mmHg). Conclusion An exaggerated orthostatic blood pressure fall in older patients with isolated systolic hypertension is associated mainly with gender, age and blood pressure level. Previous antihypertensive treatment, a lower pulse rate and a lower electrocardiographic left ventricular mass were also associated with an exaggerated orthostatic fall in systolic blood pressure.

Effects of vitamin E on the toxicity of oxidized LDL on endothelial cells in vitro in smokers vs nonsmokers on diets rich in fish

Objective:To clarify whether supplementation of vitamin E can alter the low density lipoprotein (LDL) oxidation properties and thereby affect endothelial cell function and prostacyclin production in smokers compared to nonsmokers on diets rich in fish in a pilot study.Design:The LDL of six smokers and six nonsmokers on habitual high fish diet was isolated before and after an 8-week supplementation of vitamin E (800u2009IU/day). LDL was oxidized by incubation with CuSO4. Cytotoxicity of LDL oxidized to different degrees on endothelial cells was investigated in vitro in these two groups.Setting:Helsinki University Central Hospital; Institute of Biomedicine, Pharmacology, University of Helsinki.Results:At baseline, the rate of oxidation was higher in nonsmokers than in smokers. The lag phase increased significantly after the supplementation of vitamin E both in smokers and nonsmokers. Native LDL dose dependently tended to reduce the viability of endothelial cells in vitro more markedly when isolated from smokers than from nonsmokers. Vitamin E supplementation had no beneficial effect on the cytotoxicity of oxidized LDLs in endothelial cell culture. On the other hand, simultaneous administration of Trolox®, the water-soluble analogue of vitamin E, attenuated the LDL cytotoxicity on endothelial cells. The vitamin E supplementation to LDL donors attenuated the increase in prostacyclin production both in smokers and nonsmokers.Conclusion:Supplementation of LDL donors (healthy male volunteers on habitual fish diet) with vitamin E increased the lag phase of LDL oxidation, but, on the other hand, did not influence in vitro cytotoxicity of LDL, or prostacyclin production.Sponsorship:Helsinki University Central Hospital and Biomed 2.

Oxidized LDL from subjects with different dietary habits modifies atherogenic processes in endothelial and smooth muscle cells.

Low-density lipoprotein (LDL) activates a number of processes involved in atherogenesis and vasoconstriction. Evidence suggests that oxidation increases the atherogenicity of LDL. We investigated the effects of oxidized LDL (ox-LDL) on cytotoxicity, prostacyclin (PGI2), and cyclic guanosine-3,5-monophosphate (cGMP) production in rat vascular smooth muscle cell (VSMC) and rat heart endothelial cell (EC) culture, as well as EC- and VSMC-mediated LDL oxidation. Native LDL (n-LDL) was isolated from subjects on three long-term diets with differing fatty acid content (control diet rich in saturated fat and vegetarian and fish diets). The Cu2+-catalyzed oxidation of n-LDL was monitored using conjugated diene formation and stopped at various time points to achieve 20%, 45%, 70%, and 100% levels of ox-LDL. The lag phase of oxidation by Cu2+ was shortest and thiobarbituric acid-reactive substance (TBARS) formation by VSMC-mediated oxidation was highest with n-LDL obtained from the fish diet group. There were no differences between the ox-LDLs obtained from the different diet groups in their cytotoxicity in EC culture. The degree of oxidation did not influence LDL cytotoxicity. In VSMC culture PGI2 production was increased by ox-LDLs from all diet groups. In EC culture only the extensively oxidized LDLs obtained from the vegetarian diet group were able to induce PGI2 production. The LDLs did not affect basal cGMP production in either EC or VSMC culture.

Antihypertensive therapy in elderly patients with isolated systolic hypertension : third progress report of the syst-eur trial

The Syst-Eur trial is a randomised, double-blind, placebo-controlled trial that examines the hypothesis that antihypertensive treatment can prevent or delay cardiovascular complications in elderly patients (> 60 years) with isolated systolic hypertension. On March, 1st 1993 a total of 1395 patients with a sitting systolic blood pressure on placebo averaging 160-219 mmHg and a diastolic blood pressure < 95 mmHg were randomised into this trial. The placebo and active treatment groups were similar at randomisation with respect to age (72 +/- 7 years, mean +/- SD), percentage of women (68%), percentage of patients with cardiovascular complications (30%) and sitting blood pressures (175 +/- 12/85 +/- 6 mmHg). The fall in sitting systolic and diastolic blood pressures from baseline to 2 years was significantly more pronounced (p < 0.001) in the actively treated (-22 +/- 18/-6 +/- 9 mmHg) as compared with the placebo treated Syst-Eur patients (-10 +/- 20/-1 +/- 9 mmHg). Active treatment consists of nitrendipine if necessary associated with a converting-enzyme inhibitor and a thiazide. Whether treatment with these antihypertensive agents results in a clinically meaningful reduction of cardiovascular morbidity and mortality is the subject of investigation in this trial.