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23 juin 2016

Syst-Eur? : Systolic Hypertension in Europe.

Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997 ;350(9080):757-64. 9297994

Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint.

All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat.

At a median of 2 years’ follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction ; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14% ; p = 0.22).

Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR?, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998 ;352:1347-51. 9802273

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.

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.

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).

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.

Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhäger WH ; Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment : new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002 ;162:2046-52. 12374512

After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation.

To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia.

Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs.

Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg ; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64 ; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33).

The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

De Leeuw PW, Thijs L, Birkenhäger WH, Voyaki SM, Efstratopoulos AD, Fagard RH, Leonetti G, Nachev C, Petrie JC, Rodicio JL, Rosenfeld JJ, Sarti C, Staessen JA ; Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Prognostic significance of renal function in elderly patients with isolated systolic hypertension : results from the Syst-Eur trial. J Am Soc Nephrol. 2002 ;13:2213-22. 12191965

Several reports suggest that markers of renal function such as serum creatinine, serum uric acid, and urinary excretion of protein may be related to cardiovascular complications and mortality. This study analyzed the data from the Syst-Eur trial, which was a randomized, placebo-controlled, double-blind intervention trial in elderly patients with isolated systolic hypertension. The purpose was to evaluate whether serum levels of creatinine and uric acid and urinary protein excretion at entry are related to subsequent morbidity and mortality. Incidence rates of total mortality, cardiovascular mortality, stroke (fatal as well as nonfatal), coronary events, and all cardiovascular endpoints were calculated for each quintile of serum creatinine or serum uric acid or for each category of protein excretion (none, trace, and overt). Crude and adjusted relative hazard rates were also determined for each 20 micro M increase in serum creatinine, each 50 micro M increase in serum uric acid, and for each protein excretion category. Even when adjusted for age, gender, and various other covariates, serum creatinine was significantly associated with a worse prognosis. There was an U-shaped relationship between serum uric acid and total mortality, but otherwise no obvious relationships were detected between serum uric acid levels and complications when appropriate adjustments were made for confounding variables. Proteinuria at entry was a significant predictor of total mortality and all cardiovascular endpoints. It is concluded that higher levels of serum creatinine and trace or overt proteinuria are associated with an increased number of cardiovascular events and with a higher mortality in patients with isolated systolic hypertension.