W. H. Birkenhäger

MORTALITY AND MORBIDITY RESULTS FROM THE EUROPEAN WORKING PARTY ON HIGH BLOOD PRESSURE IN THE ELDERLY TRIAL

The latter was due to a reduction in cardiac mortality (−38%, p=0.036) and a nonsignificant decrease in cerebrovascular mortality (−32%, p=0.16). In the double-blind part of the trial, the total mortality rate was not significantly reduced (−26%, p=0.077). However, cardiovascular mortality was reduced in the actively treated group (−38%, p=0.023), owing to a reduction in cardiac deaths (−47%, p=0.048) and a non-significant decrease in cerebrovascular mortality (−43%, p=0.15). Deaths from myocardial infarction were reduced (−60%, p=0.043), and study-terminating morbid cardiovascular events were significantly reduced by active treatment (−60%, p=0.0064). Non-terminating cerebrovascular events were reduced (−52%, p=0.026), but the non-terminating cardiac events were not (+ 3%, p=0.98). In the patients randomised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial.

Effects of Calcium-Channel Blockade in Older Patients with Diabetes and Systolic Hypertension

Background Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension. We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events. In this post hoc analysis, we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients. Methods After stratification according to center, sex, and presence or absence of previous cardiovascular complications, 4695 patients (age, ≥60 years) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were randomly assigned to receive active treatment or placebo. Active treatment consisted of nitrendipine (10 to 40 mg per day) with the possible addition or substitution of enalapril (5 to 20 mg per day) or hydrochlorothiazide (12.5 to 25 mg per day) or both, titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg. In the control group, matching placeb...

EFFICACY OF ANTIHYPERTENSIVE DRUG TREATMENT ACCORDING TO AGE, SEX, BLOOD PRESSURE, AND PREVIOUS CARDIOVASCULAR DISEASE IN PATIENTS OVER THE AGE OF 60

Results of the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial have been analysed in relation to age, sex, blood pressure, and previous cardiovascular disease. Cardiovascular mortality and the cardiovascular study-terminating events were significantly and independently related to treatment, age, cardiovascular complications at randomisation, and systolic but not diastolic blood pressure. The benefits of treatment observed in the trial seemed to be independent of entry blood pressure and the presence or absence of cardiovascular complications at entry. There was some evidence that treatment effect decreases with advancing age. Little or no benefit from treatment could be demonstrated in patients over the age of 80 years, the great majority of whom were women.

Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: Objectives, protocol, and organization

SummaryThe Syst-Eur Trial is a concerted action of the European Community’s Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood. Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure.To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160–219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10–40 mg/day), combined with enalapril (5–20 mg/day) and hydrochlorothiazide (12.5–25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and perprotocol comparison of the outcome in the 2 treatment groups.A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).

Placebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia

To the Editor: Hypertension at middle age is a risk factor for vascular and neurodegenerative dementia later in life.1 Because populations are aging, the number of demented patients will grow 2-fold every 20 years, from 24.3 million people in 2000 to 81.1 million by 2040, with >60% living in developing countries.2 The question of whether hypertension is a modifiable risk factor for dementia is therefore of great clinical importance. Our 2007 meta-analysis1 included 4 placebo-controlled trials of blood pressure–lowering therapies for prevention of dementia (18 196 patients and 642 dementia cases).3,–,6 The common odds ratio was 0.89 (CI, 0.75 to 1.04) and did not reach statistical significance ( P =0.15). However, sensitivity analyses revealed a difference ( P =0.04) that depended on whether active treatment started with or included a diuretic or dihydropyridine calcium channel blocker compared with an inhibitor of the renin system. The pooled …

Update on the Systolic Hypertension in Europe (Syst-Eur) Trial

The Syst-Eur trial was stopped after the second of 4 planned interim analyses, when predefined stopping rules1 revealed that active treatment diminished the incidence of stroke, the primary endpoint. The ethics committee unanimously resolved that all endpoints that had occurred before February 14, 1997, at 5 pm should be included in the final analysis. The long communication lines between the coordinating office and 198 centers in 23 countries made the practical implementation of this recommendation very difficult. The coordinating office had to strike a delicate balance between reporting long-awaited outcome results or postponing publication until a greater number of terminating report …

Noncardiogenic pulmonary edema as the sole manifestation of pheochromocytoma.

A 40-year-old man was admitted to the hospital with pulmonary edema without signs of left ventricular failure. Noncardiogenic pulmonary edema was diagnosed, and a subsequent workup identified a pheochromocytoma as the cause of this condition. The clinical picture could be mimicked by infusion of exogenous norepinephrine. It is concluded that surges of catecholamines from a pheochromocytoma may provoke pulmonary edema in a manner similar to that by which neurogenic pulmonary edema related to cerebral disorders occurs.

Renal response to propranolol treatment in hypertensive humans.

To investigate the relationship between sympathetic activity and blood flow in the kidney during propranolol treatment, 55 patients with uncomplicated essential hypertension were studied. Twenty-five of them had been treated with propranolol (average daily dose 240 mg) for about two weeks; the others served as untreated controls. In all patients renal arteriography was carried out, after which renal plasma flow (125I-hippuran clearance), cortical blood flow (xenon-washout), and renal release of norepinephrine and renin were measured. In the propranolol group, renal plasma flow had also been determined before treatment. Cardiac output (dye-dilution) and creatinine clearance were measured both before as well as during therapy. In untreated hypertensives renal cortical blood flow was reduced to about 80% of what was predicted for the age level. On the basis of their changes in blood pressure, patients who were treated with propranolol were divided into responders (n = 15) and nonresponders (n = 10). Despite a similar fall in cardiac output in both subgroups, renal blood flow remained unchanged in responders, while it fell in nonresponders. In addition, renal norepinephrine release was significantly higher in nonresponders than in responders, while renin release in nonresponders was markedly suppressed. It may be concluded that sympathetic activity is an important determinant of renal (cortical) blood flow in essential hypertension. The effect of propranolol on the renal circulation depends, to some extent, on its unmasking of prevailing alpha-adrenergic tone. However, when blood pressure falls, an additional mechanism may be operative to cause renal vasodilation.

Glucose intolerance during diuretic therapy in elderly hypertensive patients. A second report from the European Working Party on high blood pressure in the elderly (EWPHE).

Five hundred and seven elderly hypertensive patients were followed for 1 year, 371 for 2 years and 270 for 3 years in a double-blind, randomized, controlled trial in which they received either placebo or 25-50 mg hydrochlorothiazide and 50-100 mg of triamterene daily. One third of the active treatment group also received 250 mg to 2 g methyldopa daily. After 1 year the active treatment group had an average increase in fasting blood sugar of 2.5 mg/dl compared with an average fall of 1.4 mg/dl in the placebo group (P = 0.01). The increase in blood sugar 1 hour and 2 hours after 50 g oral glucose tended to be greater in the actively treated group but these increases did not achieve statistical significance. The effects of diuretic treatment were established after one year and did not increase further over the next 2 years. Overall there was an increase in fasting blood sugar of 5 mg/dl in the active treatment group which occurred mainly in the first year. The hyperglycaemic effect of diuretics appeared to be partly or wholly related to potassium loss since, in both groups, impairment of glucose tolerance was most marked in those in whom serum potassium decreased. The measures of blood sugar were also positively related to systolic pressure before and after treatment.

Systolic Hypertension in Europe (Syst-Eur) Trial Phase 2: objectives, protocol, and initial progress

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 (⩾60 years) patients with isolated systolic hypertension (systolic BP ⩾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% Cl: 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.