MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party.

The main aim of the trial was to determine whether drug treatment of mild hypertension (phase V diastolic pressure 90-109 mm Hg) reduced the rates of stroke, of death due to hypertension, and of coronary events in men and women aged 35-64 years. Subsidiary aims were: to compare the course of blood pressure in two groups, one taking bendrofluazide and one taking propranolol, and to compare the incidence of suspected adverse reactions to these two drugs. The study was single blind and based almost entirely in general practices; 17 354 patients were recruited, and 85 572 patient years of observation have accrued. Patients were randomly allocated at entry to take bendrofluazide or propranolol or placebo tablets. The primary results were as follows. The stroke rate was reduced on active treatment: 60 strokes occurred in the treated group and 109 in the placebo group, giving rates of 1.4 and 2.6 per 1000 patient years of observation respectively (p less than 0.01 on sequential analysis). Treatment made no difference, however, to the overall rates of coronary events: 222 events occurred on active treatment and 234 in the placebo group (5.2 and 5.5 per 1000 patient years respectively). The incidence of all cardiovascular events was reduced on active treatment: 286 events occurred in the treated group and 352 in the placebo group, giving rates of 6.7 and 8.2 per 1000 patient years respectively (p less than 0.05 on sequential analysis). For mortality from all causes treatment made no difference to the rates. There were 248 deaths in the treated group and 253 in the placebo group (rates 5.8 and 5.9 per 1000 patient years respectively). Several post hoc analyses of subgroup results were also performed but they require very cautious interpretation. The all cause mortality was reduced in men on active treatment (157 deaths versus 181 in the placebo group; 7.1 and 8.2 per 1000 patient years respectively) but increased in women on active treatment (91 deaths versus 72; 4.4 and 3.5 per 1000 patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05). Comparison of the two active drugs showed that the reduction in stroke rate on bendrofluazide was greater than that on propranolol (p = 0.002). The stroke rate was reduced in both smokers and non-smokers taking bendrofluazide but only in non-smokers taking propranolol. This difference between the responses to the two drugs was significant (p = 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)     

Relation between dose of bendrofluazide,antihypertensive effect,and adverse biochemical effects.

OBJECTIVE--To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension. DESIGN--Double blind parallel group trial of patients who were given placebo for six weeks and then randomly allocated to various doses of bendrofluazide (1.25, 2.5, 5, or 10 mg daily) or placebo for 12 weeks. SETTING--General practices in Zealand, Denmark. PATIENTS--257 Patients with newly diagnosed or previously treated hypertension, aged 25-70, who had a mean diastolic blood pressure of 100-120 mm Hg after receiving placebo for six weeks. MAIN OUTCOME MEASURES--Reduction in diastolic blood pressure and changes in biochemical variables (potassium, urate, glucose, fructosamine, total cholesterol, apolipoprotein A I, apolipoprotein B, and triglyceride concentrations). RESULTS--All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree (10-11 mm Hg). Clear relations between dose and effect were shown for potassium, urate, glucose, total cholesterol, and apolipoprotein B concentrations. The 1.25 mg dose increased only urate concentrations, whereas the 10 mg dose affected all the above biochemical variables. CONCLUSION--The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25-2.5 mg a day. Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects. Previous trials with bendrofluazide have used too high doses.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Atenolol and bendrofluazide in hypertension.

The effect of atenolol, a new beta-1-adrenergic receptor blocking agent, was studied in a double-blind cross-over trial in 24 carefully selected hypertensive outpatients. After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day, atenolol 400 mg/day, a combination of atenolol 200/mg day with bendrofluazide 5 mg/day, and bendrofluazide 5 mg/day alone, according to a random sequence. Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except standing systolic pressure than bendrofluazide alone. There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate. The addition of bendrofluazide to atenolol resulted in a further significant lowering of the blood pressure. A significant effect of thiazide on weight was noted. The study shows that atenolol, a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity, is an effective and well-tolerated hypotensive agent.     

Controlled Trial of Propranolol in Hypertension

A trial of oral propranolol as a hypotensive agent was designed to provide adequate treatment periods. Twenty-eight patients with essential hypertension, with a mean blood pressure of 190/111 mm. Hg, were controlled on 120-320 mg. of propranolol daily. Their mean treated blood pressure was 153/91. They then entered, on a randomized and double-blind basis, a cross-over trial of two 16-week periods, blood pressure being measured fortnightly. Propranolol caused a statistically significant fall in blood pressure when compared with placebo. When propranolol was withdrawn blood pressures rapidly rose to hypertensive levels, though not to untreated levels. No postural hypotension was found, but a small change in blood pressure levels on exercise was noted.     

Comparison of natriuretic,uricosuric, and antihypertensive properties of tienilic acid,bendrofluazide, and spironolactone.

The antihypertensive properties of the new diuretic tienilic acid were investigated. Thirteen previously untreated hypertensive patients took part in a double-blind crossover study in which 30 days'' treatment with tienilic acid 250 mg, bendrofluazide 5 mg, and spironolactone 100 mg were compared. Bendrofluazide caused the greatest natriuresis on the first treatment day and the most rapid fall in blood pressure. The ultimate antihypertensive effect of all three drugs was similar. Tienilic acid caused a noticeable reduction in serum urate concentrations and a rise in urate clearance, in contrast to the other two agents, which caused slight urate retention. Tienilic acid and bendrofluazide caused falls and spironolactone a rise in plasma potassium concentrations. No untoward effects were seen from any of the drugs. It is concluded that tienilic acid is a moderately potent diuretic that lowers plasma urate concentrations. It may be the drug of first choice for hypertensive patients who already have gout or are likely to develop it when taking thiazide diuretics.     

Efficacy of potassium and magnesium in essential hypertension: a double-blind,placebo controlled,crossover study.

OBJECTIVE--To evaluate the antihypertensive activity of potassium given alone or in combination with magnesium in patients with mild hypertension. DESIGN--A double blind, randomised, placebo controlled, crossover trial of 32 weeks'' duration. SETTINGS--Cardiology outpatient department, Sassoon General Hospitals, Pune, India. PATIENTS--37 Adults with mild hypertension (diastolic blood pressure less than 110 mm Hg). INTERVENTION--Patients received either placebo or potassium 60 mmol/day alone or in combination with magnesium 20 mmol/day in a crossover design. No other drug treatment was allowed. MEASUREMENTS--Blood pressure and heart rate assessed at weekly intervals and biochemical parameters at monthly intervals. RESULTS--Potassium alone or in combination with magnesium produced a significant reduction in systolic and diastolic blood pressures (p less than 0.001) and a significant reduction in serum cholesterol concentration (p less than 0.05); other biochemical variables did not change. Magnesium did not have an additional effect. Urinary potassium excretion increased significantly in the groups who received potassium alone or in combination with magnesium. The drug was well tolerated and compliance was satisfactory. CONCLUSION--Potassium 60 mmol/day lowers arterial blood pressure in patients with mild hypertension. Giving magnesium as well has no added advantage.     

Mild hypertension: a clinical trial conducted in hospital general practice.

To compare findings in a hospital trial of hypotensive drugs with those in a general practice trial several patients with mild hypertension were studied at the same time in hospital and in general practice. They received bendrofluazide and potassium chloride or bendrofluazide, potassium chloride, and reserpine according to a double-blind crossover protocol, and blood biochemical values were studied over eight weeks and six months. When reserpine was withdrawn from nine women they followed a modified protocol comparing bendrofluazide and potassium chloride with potassium chloride alone. The blood pressure values measured by the general practitioners were similar to those measured in hospital. Both the diuretic alone and the diuretic with reserpine produced significant falls in blood pressures. Although plasma renin activity increased on diuretic treatment, continued treatment did not produce a further increase, and levels gradually declined towards normal.     

The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide.

In a double blind placebo controlled randomised parallel study the antihypertensive activity and adverse biochemical effects of three doses of cyclopenthiazide were evaluated in patients with mild essential hypertension that had been recently diagnosed or was being treated with a single drug. After a four week placebo washout period 53 patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to 50, 125, or 500 micrograms cyclopenthiazide or matching placebo for an eight week period of treatment. Blood pressure was measured in the patients'' homes by the same observer every two weeks. Serum urea, electrolytes, urate, and creatinine concentrations and 24 hour urinary sodium excretion were monitored every four weeks and serum magnesium concentration and plasma renin activity at the end of the washout and treatment periods. After eight weeks of treatment systolic and diastolic blood pressures were significantly reduced in patients taking 125 and 500 micrograms cyclopenthiazide when compared with those taking placebo. The decrement in serum potassium concentration (0.6 mmol/l) and increase in serum urate concentration 0.06 mmol/l) were greatest with the 500 micrograms dose, the increase in serum urate concentration alone being significant. No change in serum magnesium concentration or 24 hour urinary sodium excretion was noted with any dose of cyclopenthiazide. Only the 500 micrograms dose of cyclopenthiazide significantly increased the mean plasma renin activity (1.8 (95% confidence interval 0.2 to 3.4)-5.4 (3.9 to 6.8) nmol angiotensin I/l/h); the other doses like the placebo had no effect. Cyclopenthiazide 125 micrograms, a dose lower than is currently marketed, produced a similar hypotensive response to 500 micrograms of the drug without upsetting the biochemical profile.     

Ventricular extrasystoles during thiazide treatment: substudy of MRC mild hypertension trial.

One short term and one long term study of the relation between ventricular extrasystoles and thiazide treatment were carried out during the Medical Research Council''s mild hypertension trial. In the short term study 110 patients were randomly assigned to one of three treatment groups, bendrofluazide with or without potassium supplements, or placebo. They were studied before starting treatment and nine to 10 weeks later while still taking their randomly assigned drugs. No significant increase in the number of ventricular extrasystoles was associated with short term thiazide treatment, although serum potassium concentrations changed as expected. In the long term study 214 patients who had completed an average of two years'' treatment with randomly assigned bendrofluazide or a placebo were studied while continuing to take their trial tablets; the 214 included 20 people who had been randomised at entry to the bendrofluazide group and who had a subsequent history of hypokalaemia. These 20 patients were studied before and after being further randomised to two groups, one continuing treatment without change and one continuing with bendrofluazide and also taking potassium supplements. Counts of ventricular extrasystoles were significantly higher (p = 0.025) in those receiving long term thiazide treatment than in their controls; however, there was no significant association between the number of ventricular extrasystoles and serum potassium concentrations in this group, although the correlation between number of extrasystoles and serum urate concentrations was significant (p = 0.035). Pooled data for both studies showed a highly significant correlation between number of ventricular extrasystoles, and serum potassium concentrations (r = -0.185; p = 0.003), but the correlation with serum urate concentrations was of similar strength (r = 0.178; p = 0.004). These biochemical changes may be acting merely as markers of thiazide intake, and the explanation of the association between thiazide treatment and ventricular extrasystolic activity therefore remains uncertain.     

Anabolic steroids in athelics: crossover double-blind trial on weightlifters.

Thirteen experienced male weightlifters taking high-protein diets and regular exercise took part in a double-blind crossover trial of methandienone 10 or 25 mg/day to seeif the drug improved athletic performance. Their improvemments were significantly greater on methandienone than on placebo; their body weights rose (though this seemed to be associated with water retention); and systolic blood pressure rose significantly. Methandienone caused many side effects, and three men had to withdraw because of them. All side effects disappeared after the drug was stopped. Anabolic steroids are effective only when given combination with exercise and high-protein diet.We deprecate their use in athletics but can suggest no way of stopping it.     

Increased resting metabolic rate and lipid oxidation in exercise-trained individuals: evidence for a role of beta-adrenergic stimulation.

This study investigated the contribution of beta-adrenergic stimulation to the increase in resting metabolic rate (RMR) and lipid oxidation observed in exercise-trained individuals. Nine trained and eight sedentary men were subjected to two testing sessions, during which these variables were measured before and for 3 h after the oral administration of propranolol or placebo. As expected, RMR and lipid oxidation were significantly higher in the trained subjects before the administration of propranolol and throughout the placebo test in comparison with sedentary controls. A significant decrease in RMR and lipid oxidation was induced by propranolol in the trained subjects, whereas no change was observed in the untrained group, and this effect of propranolol was sufficient to abolish the difference between the two groups at baseline and under the placebo condition. Propranolol also induced a significant reduction in heart rate and systolic blood pressure, but the response was comparable in the two groups. In conclusion, the results of this study show that beta-adrenergic stimulation is involved in the increase in RMR and lipid oxidation observed in highly trained individuals. Moreover, the absence of a training-propranolol interaction effect on heart rate and systolic blood pressure suggests the existence of some dissociation between the metabolic and cardiovascular effects of prolonged exercise training.     

Stroke and coronary heart disease in mild hypertension: risk factors and the value of treatment

Further analyses of the Medical Research Council''s trial of drug treatment of mild hypertension were carried out to provide more detailed information on the benefits associated with treatment in various subgroups. The four main considerations in establishing a rational treatment policy were, firstly, the significant reduction in the stroke rate with active treatment; secondly, the absence of a significant overall treatment effect on myocardial infarction; thirdly, the knowledge that of 100 untreated men in the highest risk group (those aged 55-64 with high systolic pressure at entry who smoked), five would be expected to suffer a stroke and 10 a coronary event within five years; and, fourthly, the cost, in clinical and financial terms, of prolonged treatment. In the high risk group of 100 men treatment with bendrofluazide would result in the prevention of three or four of the five strokes but would have little effect on the expected numbers of myocardial infarctions. Treatment with propranolol in non-smoking men in the highest age and blood pressure categories would lead to a reduction in the number having strokes from three to one or two and might possibly reduce the number experiencing myocardial infarction from seven to four. Smokers treated with propranolol would not be expected to benefit. In women avoiding smoking was particularly important. The considerations for preventing stroke were similar to those in men, but no clear guideline was possible on the effect of lowering blood pressure for preventing myocardial infarction in women.Drug treatment reduces the attack rate of certain events in mild hypertension but should not be prescribed routinely for all patients with the disorder.     

Methyldopa and propranolol or practolol in moderate hypertension.

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.     

Attenuation of hypotensive effect of propranolol and thiazide diuretics by indomethacin.

The effects of 100 mg indomethacin daily for three weeks on blood pressure and urinary excretion of prostaglandin F2 alpha were studied in a double-blind, placebo-controlled comparison of two groups of patients with essential hypertension, eight receiving propranolol and seven thiazide diuretics. Compared with placebo, adding indomethacin to the patients'' established antihypertensive treatment increased blood pressure by 14/5 Hg supine and 16/9 mm Hg erect in the patients receiving propranolol, and by 13/9 mm Hg supine and 16/9 mm Hg erect in the patients receiving thiazide diuretics (all p less than or equal to 0.05). The excretion of the major urinary metabolite of prostaglandin F2 alpha was reduced by 67% in the propranolol-treated patients and by 57% in those receiving a thiazide diuretic. Body weight increased by 0 . 8 kg (propranolol) and 1 . 1 kg (thiazide diuretic) when indomethacin was given, but there were no significant changes in creatinine clearance, urinary sodium excretion, or packed cell volume in either treatment group. These results suggest that products formed by the arachidonic acid cyclo-oxygenase contribute to the regulation of blood pressure during treatment with both propranolol and thiazide diuretics. Inhibition of the cyclo-oxygenase with indomethacin partially antagonises the hypotensive effect of these drugs.     

Natural progesterone and antihypertensive action.

In a placebo controlled, double blind crossover study natural progesterone was given by mouth, in increasing doses, to six men and four postmenopausal women with mild to moderate hypertension who were not receiving any other antihypertensive drugs. When compared with values recorded before treatment and during administration of placebo progesterone caused a significant reduction in blood pressure, suggesting that progesterone has an antihypertensive action rather than a hypertensive one as has been previously thought. This possible protective effect of progesterone should be investigated further.     

Effects of an angiotensin-converting enzyme inhibitor (captopril) on blood pressure in anephric subjects.

Randomised, double-blind cross-over trials were performed in seven anephric patients to determine the effect of the orally active angiotensin-converting enzyme inhibitor captopril on blood pressure in fluid-depleted and fluid-replete patients. Patients were given captopril, 100 mg orally, or placebo one hour after haemodialysis, when they were fluid depleted. Their mean (+/- SEM) supine blood pressure fell from 127 +/- 12/71 +/- 6 mm Hg before captopril to 106 +/- 13/54 +/- 4 mm Hg 24 hours after the drug, while on placebo it rose from 123 +/- 11/73 +/- 5 mm Hg to 134 +/- 10/82 +/- 8 mm Hg. All patients developed orthostatic hypotension after captopril. In the fluid-replete state, two days after haemodialysis, captopril had no effect on blood pressure. The plasma concentration of active renin was extremely low and did not rise after fluid withdrawal or captopril. Thus the hypotensive effect of captopril did not appear to depend on circulating renin concentrations. The concept of "renin-dependent" hypertension, which is responsive to captopril, as opposed to "volume-dependent" hypertension, which is not responsive to captopril, may therefore be invalid.     

β-Blockers and Plasma Renin Activity in Hypertension

Long-term treatment with propranolol was shown to produce a sustained suppression of the renin-aldosterone system in hypertensive patients, despite concurrent diuretic treatment. However, the antihypertensive effect of this treatment correlated poorly with its effects on plasma renin activity and urinary aldosterone excretion. When prindolol, another β-adrenergic blocking drug, was substituted for propranolol, blood pressure control was retained, but there was a prompt rise in plasma renin activity, which was not attributable to changes in electrolyte balance. These observations suggest that the antihypertensive action of propranolol and other β-blockers does not result from their effects on plasma renin activity.     

Long term reduction in sodium balance: possible additional mechanism whereby nifedipine lowers blood pressure.

OBJECTIVE--To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine. DESIGN--Single blind, placebo controlled study in patients receiving fixed sodium and potassium intakes. SETTING--Blood pressure unit of a teaching hospital in south London. PATIENTS--Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks. INTERVENTIONS--Withdrawal of nifedipine and replacement with matching placebo for one week. MAIN OUTCOME MEASURES--Urinary sodium excretion and cumulative sodium balance, body weight, plasma atrial natriuretic peptide concentrations, plasma renin activity and aldosterone concentrations, and blood pressure. RESULTS--During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo, and the rise seemed to be related to the amount of sodium that was retained. CONCLUSIONS--Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.     

Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.

OBJECTIVE--To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses. DESIGN--Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period. SETTING--Outpatient clinics serving the greater Belfast area. SUBJECTS--16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area. MAIN OUTCOME MEASURES--Systolic and diastolic blood pressure and peripheral and hepatic insulin action. RESULTS--One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline. CONCLUSIONS--Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.