Healing and prevention of relapse of reflux oesophagitis by cisapride.

Altogether, 138 patients were included in a study aimed at evaluating the effect of cisapride on healing and relapse of oesophagitis shown endoscopically. In the first phase of the study cisapride was given in an open fashion at 10 mg four times a day for 8 to 16 weeks, and healing was obtained in 69% of patients. Healing occurred later in patients with grades II to IV oesophagitis. The total score for reflux symptoms decreased by 67%. Eighty of the healed patients were included in the second phase. They were randomly assigned to double blind treatment with either cisapride 10 mg (n = 37) or placebo (n = 43) twice a day. Control endoscopy was performed when symptoms recurred or at the end of the six month trial. The cumulative percentage of patients in remission was higher (p = 0.06, survival analysis) in the cisapride group than in the placebo group, the relapse rates being 20% and 39%. The duration of remission tended to be longer in patients with a lower initial degree of oesophagitis. Adverse effects were no more frequent with cisapride than with placebo. In conclusion, cisapride is efficacious in healing oesophagitis, and, unlike other gastrointestinal prokinetic drugs or low dose cimetidine (400-800 mg daily) or ranitidine (150 mg daily), it may prevent relapse of oesophagitis.

A double-blind comparison of perindopril and hydrochlorothiazide-amiloride in mild to moderate essential hypertension.

The aim of this 3-month double-blind multicenter trial was to compare the antihypertensive efficacy and tolerability of the ACE inhibitor perindopril with those of a diuretic combination. After 1 month of receiving placebo, 165 patients with essential hypertension were randomised to perindopril 4 mg (n = 82) or to 50 mg hydrochlorothiazide + 5 mg amiloride (n = 83). The patients were treated for 3 months with monthly assessments, "uncontrolled" patients (DBP greater than 90 mm Hg) had their dosage doubled and then, if necessary, atenolol 50 mg was added. At the end of the 3-month study, mean decreases in supine and standing systolic and diastolic blood pressures were similar in both groups. In the perindopril group, BP control was obtained in 56% of the patients with the 4 mg dosage and required an increase to 8 mg alone in 16% and with atenolol in 5%. The corresponding percentages in the diuretic group were 48, 23 and 13%. The overall percentage of "controlled" patients was similar in the 2 groups, respectively 78 and 84%. The nature and incidence of complaints were comparable in the 2 groups. Adverse laboratory changes were more frequent in the diuretic group: decrease in blood sodium (140.5 vs 139.1 mmol/l; P less than 0.01), potassium (4.2 vs 3.9 mmol/l; P less than 0.01) with 10 patients having significant hypokalemia, increase in blood urea, triglycerides and uric acid. By contrast, a transient increase in blood potassium with a decrease in triglycerides was observed in the perindopril group.

Is a high serum cholesterol level associated with longer survival in elderly hypertensives?

The relationship between serum total cholesterol, measured at randomization, and mortality was investigated in 822 patients, who were followed for an average of 3.1 years in a double-blind trial, conducted by the European Working Party on High Blood Pressure in the Elderly. Serum cholesterol, measured at randomization, was 0.54 mmol/l higher in women than in men, and declined with increasing age in both men (0.028 mmol/l per year) and women (0.036 mmol/l per year). During follow-up on randomized treatment, cholesterol fell by a similar amount with placebo (0.11 mmol/l per year) and with active treatment (0.14 mmol/l per year). Active treatment consisted of hydrochlorothiazide (25-50 mg/day) plus triamterene (50-100 mg/day) with the addition of alpha-methyldopa (0.5-2.0 g/day) in one-third of the patients. Serum total cholesterol, measured at randomization, was independently and inversely correlated with total (P = 0.03), non-cardiovascular (P = 0.03) and cancer (P = 0.04) mortality during follow-up on double-blind treatment. Total and non-cardiovascular mortality were also negatively correlated with haemoglobin and body weight at randomization.

Diuretics--a risk in the long-term treatment of hypertensive patients?

The trial of the European Working Party on High blood pressure in the Elderly (EWPHE) revealed an overall decrease in cardiovascular mortality and morbidity in the actively treated patients. They received as first-line drugs a combination of hydrochlorothiazide and triamterene; methyldopa was added as necessary. The present post hoc analysis examined the effect of the diuretic treatment on cardiovascular events, both when given alone and in conjunction with methyldopa, by calculating the relative hazard rates (RHR) for cardiovascular mortality and morbidity. Using the Cox proportional hazard model, compared with placebo, a 34% reduction in cardiovascular mortality in the intention-to-treat analysis was demonstrated in the diuretic (hydrochlorothiazide and triamterene) group with an RHR of 0.66 and a 95% confidence interval (CI) of 0.44-0.97; the 16% decrease in the group treated with diuretics and methyldopa was not significant (RHR, 0.84; 95% CI, 0.56-1.25). The effect of treatment in the latter combined group became significant (RHR, 0.62; 95% CI, 0.40-0.95) when all cardiovascular study terminating events were considered; they were reduced by 38%. No effect of treatment on mortality from all causes was detected.

Cisapride in the management of chronic functional dyspepsia: a multicenter, double-blind, placebo-controlled study.

The effects of cisapride, a nondopaminolytic motility-enhancing agent, were studied in 56 patients with chronic functional dyspepsia; all had symptoms suggestive of delayed gastric emptying. The patients received 4 mg or 8 mg of cisapride or placebo orally three times daily for two successive three-week periods according to a randomized, double-blind, crossover study design. Although there was a high placebo response (55% showed good or excellent results), the global response to treatment was significantly (P = 0.024) in favor of cisapride (75% had good or excellent results). The drug was particularly superior to placebo (P = 0.03) in the improvement of a cluster of symptoms typical of postprandial discomfort, including early satiety and nausea. Side effects were minimal.

Influence of antihypertensive drug treatment on morbidity and mortality in patients over the age of 60 years. European Working Party on High blood pressure in the Elderly (EWPHE) results: sub-group analysis on entry stratification.

The European Working Party on High blood pressure in the Elderly (EWPHE) trial was a double-blind randomized placebo-controlled trial of antihypertensive treatment in patients over the age of 60 years. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range of 90-119 mmHg and a systolic blood pressure in the range of 160-239 mmHg. Eight-hundred and forty patients were randomly assigned either to active treatment (hydrochlorothiazide + triamterene) or a matching placebo. If blood pressure remained elevated methyldopa was added to the active regimen and matching placebo to the placebo regimen. Before randomization, the patients were stratified in eight strata according to sex, age groups between 60 and 69 years or 70 years and over, and the presence or absence of cardiovascular complications of hypertension. Both the intention-to-treat and 'on randomized treatment' analyses suggested a benefit from active treatment in men and women. Formal statistical significance was achieved for male cardiovascular mortality (intention-to-treat analyses) and for cardiovascular events in females. Although the event rates were greater for patients with previous cardiovascular events and patients over the age of 70 years, the percentage reduction in cardiovascular events was similar in these groups to those without complications and in patients between 60 and 69 years of age. However, little benefit from treatment could be demonstrated in patients over the age of 80 years. The presence or absence of smoking had no influence on response to treatment in these elderly patients.

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.

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.

Influence of hypotensive drug treatment in elderly hypertensives: study terminating events in the trial of the European Working Party on High Blood Pressure in the Elderly.

The European Working Party on High Blood Pressure in the Elderly (EWPHE) trial was a double-blind randomized placebo-controlled trial of antihypertensive treatment in patients over the age of 60 years. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90-119 mmHg and a systolic blood pressure in the range of 160-239 mmHg. The patients (n = 840) were randomized either to active treatment (hydrochlorothiazide + triamterene) or matching placebo. If the blood pressure remained elevated, methyldopa was added to the active regimen and matching placebo in the placebo group. An overall intention-to-treat analysis, combining the double-blind part of the trial and all subsequent follow-up, revealed a non-significant change in total mortality rate (-9%, P = 0.41) but a significant reduction of cardiovascular mortality rate (-27%, P = 0.037). The latter was due to a reduction of cardiac mortality (-38%, P = 0.036) and to a non-significant decrease of cerebrovascular mortality (-32%, P = 0.16). In the double-blind part of the trial, total mortality rate was not significantly reduced (-26%, P = 0.077). Cardiovascular mortality was reduced in the actively treated group (-38%, P = 0.023), due to a reduction of cardiac deaths (-47%, P = 0.048) and to a non-significant decrease of cerebrovascular mortality (-43%, P = 0.15). Deaths from myocardial infarction were reduced (-60%, P = 0.043). Study-terminating morbid cardiovascular events were significantly reduced by active treatment (-60%, P = 0.0064). In the patients randomized to active treatment there were 14 fewer cardiovascular deaths per 1000 patient-years during the double-blind part of the trial. Version 3.

Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial.

A double-blind randomised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90-119 mm Hg and a systolic pressure in the range 160-239 mm Hg. 840 patients were randomised either to active treatment (hydrochlorothiazide + triamterene) or to matching placebo. If the blood pressure remained raised, methyldopa was added to the active regimen and matching placebo in the placebo group. An overall intention-to-treat analysis, combining the double-blind part of the trial and all subsequent follow-up, revealed a non-significant change in total mortality rate (-9%, p = 0.41) but a significant reduction in cardiovascular mortality rate (-27%, p = 0.037). The latter was due to a reduction in cardiac mortality (-38%, p = 0.036) and a non-significant decrease in cerebrovascular mortality (-32%, p = 0.16). In the double-blind part of the trial, total mortality rate was not significantly reduced (-26%, p = 0.077). 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). 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.

Antihypertensive therapy in patients above age 60 with systolic hypertension. A progress report of the European Working Party on High Blood Pressure in the Elderly (EWPHE).

1. Although systolic blood pressure elevation is responsible for increased incidence of cardiovascular accidents in old people, the preventive benefit of lowering systolic hypertension in elderly has not been confirmed. 2. A double blind study comparing the effects of a placebo and of an active regimen (hydrochlorothiazide-triamterene with or without methyldopa) in people over 60 years with isolated systolic hypertension has been undertaken by the European Working Party on High blood pressure in the Elderly (EWPHE). 3. The actively treated group shows a lowered sitting blood pressure (-15/6 mm Hg), a mild increase of serum creatine, serum uric acid and blood glucose and a mild decrease of serum potassium after two years of treatment when compared to the spontaneous changes observed in the placebo treated group. 4. The study is continuing to evaluate if the blood pressure reduction prevents or reduces the incidence of cardiovascular accidents, although some biochemical changes were provoked by the treatment.

Influence of anti-hypertensive therapy on serum cholesterol in elderly hypertensive patients. Results of trial by the European Working Party on High blood pressure in the Elderly (EWPHE).

In the European Working Party trial on High blood pressure in the Elderly, patients over 60 are randomly allocated either to receive diuretic capsules containing 25 mg hydrochlorothiazide and 50 mg triamterene or matching placebos. If the blood pressure remains high those receiving active diuretic treatment also receive methyldopa. Those receiving a placebo diuretic area given placebo methyldopa tablets. The study is double blind, started in 1974 and is still in progress. Three hundred and thirty-one patients have now been followed for 1 year and of these 190 have been followed for 2 and 90 for 3 years. After 1 year the serum cholesterol in the placebo group fell by an average of 10.4 mg/100 ml; over 2 years the fall was 16.0 mg/100 ml and over 3 years 20.8 mg/100 ml (6.7%). The corresponding results for the actively treated group were falls of 3.1 mg/100 ml; 20.3 mg/100 ml and 17.3 mg/100 ml (6.6%). Over a period of up to 3 years the average fall in cholesterol was 5.9 mg/100 ml/year in the placebo group and 5.0 mg/100 ml/year in the actively treated group. Thus the changes in serum cholesterol were similar whether the patients received active or placebo medication. In particular there was no evidence for an increase in cholesterol nor for a smaller decrease during diuretic therapy. In the actively treated group the fall in blood pressure in the more hypertensive patients was accompanied by a fall both in haematocrit and serum cholesterol. In patients with less severe hypertension, active treatment was not accompanied by a fall in either hematocrit or cholesterol. These different responses of serum cholesterol in the more and less severe hypertensives in the present study could explain some of the previous conflicting reports on the influence of diuretic treatment on serum cholesterol.

Glucose intolerance during diuretic therapy. Results of trial by the European Working Party on Hypertension in the Elderly.

119 elderly, hypertensive patients were followed-up for 1 year and 48 for 2 years in a double-blind, randomised, controlled trial in which they received either placebo or 25-50 mg hydrochlorothiazide and 50-100 mg of triamterene daily. Half of the active treatment group also received 250 mg to 2 g methyldopa daily. After 2 years the active treatment group had an average increase in fasting blood-sugar of 9.6 mg/dl compared with an average fall of 3.1 mg in the placebo group (p less than 0.001). Blood-glucose rose by an average of 26.6 mg/dl in the active group when determined 1 hour after 50 g oral glucose and decreased by an average of 5.3 mg/dl in patients who had been on placebo for two years (p less than 0.05). The hyperglycaemic effect of diuretics appeared to be related to potassium loss since, in both groups, impairment of glucose tolerance was most marked in those in whom the serum-potassium decreased over the 2 years.

Antihypertensive therapy in patients above age 60. Third interim report of the European Working Party on High blood pressure in Elderly (EWPHE).

Three hundred forty nine hypertensive patients above the age of 60 have entered the double-blind multicentre trial of the European Working Party on High blood pressure in the Elderly (EWPHE). After stratification and randomisation half were treated with one or two capsules containing 25 mg hydrochlorothiazide and 50 mg triamterene and if blood pressure control was insufficient methyldopa was added up to 2 g daily; the other half received matching placebo. No significant differences between the groups were present prior to randomisation. A significant blood pressure difference of 25/10 mm Hg was obtained between the groups and maintained during two years of follow-up. No major disturbances in serum potassium or serum sodium were noted with the present drug combination. However, during the initial phase an increase in serum creatinine and serum uric acid was noted in the actively treated group, which was maintained for two years. Also glucose tolerance was impaired after 2 years in the actively treated group. A favourable influence on prognosis by active treatment can be expected on the basis of the blood pressure reduction and in the absence of major electrolytes disturbances. But this benefit must be proven by observed statistical differences in terminating events between the groups. Therefore the patients are being followed for a longer period of time and more patients are admitted into the trial.