Panel discussion. I.II: Who is concerned with patient welfare in research?
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Clinical Trials as Topic↗
Biomedical subjects
C Dollery
Publications and source records attributed to C Dollery.
The Medical Research Council Hypertension Trial: the smoking patient.
Tobacco smoking is a powerful risk predictor for coronary disease. In the recent Medical Research Council (MRC) Hypertension Trial, which this article discusses, it also proved to be an important predictor of stroke. The MRC trial had two active treatment groups, one of which received bendrofluazide and the other propranolol. The main positive result of the trial was a 45% reduction in stroke events in the actively treated groups. Propranolol appeared to be much less effective than bendrofluazide in the prevention of stroke in smokers, although both active drugs were equally effective in nonsmokers. Possible explanations for this lack of efficacy in smokers are discussed. Coronary events were not reduced by treatment, although there was a trend toward their reduction in nonsmoking men treated with propranolol. The lack of effect of propranolol in reducing coronary morbidity and mortality rates was a surprise in view of the positive results from trials with both short-term and long-term treatment with beta-adrenergic blockade after myocardial infarction.
Adult↗
Calcium antagonists alone or in combination in today's antihypertensive therapy.
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Aging↗
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.
Aged↗
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.
Age Factors↗
Interaction of nonsteroidal anti-inflammatory drugs with antihypertensive and diuretic agents. Control of vascular reactivity by endogenous prostanoids.
Indomethacin and some other nonsteroidal anti-inflammatory drugs partially antagonize the blood pressure lowering effect of drugs used to treat hypertension. They can also produce a mild elevation of blood pressure in normotensive individuals. The elevated arterial pressure caused by these agents is associated with increases in the vascular resistance of mainly the renal and splanchnic beds. This may be due to direct inhibition of the synthesis of vasodilator prostanoids, or it may be due to indirect potentiation of the action of the sympathetic nervous system or of angiotensin II. Nonsteroidal anti-inflammatory drugs also cause renal retention of sodium and this probably contributes to their hypertensive effects. In humans, the sodium retention may involve increased reabsorption in the proximal tubule. Although a direct tubular action is possible, these drugs may change proximal sodium reabsorption by their vascular effects. However, the exact mechanism is not understood. These interactions are clinically significant and may complicate the treatment of common diseases.
Animals↗
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.
Aged↗
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.
Actuarial Analysis↗
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.
Aged↗
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.
Aged↗
Enhanced noradrenaline response in cardiomyopathic hamsters: possible relation to changes in adrenoceptors studied by radioligand binding.
To assess the possible relation between catecholamine responses and adrenoceptor affinity and density, we compared the effect of noradrenaline, isoprenaline and ouabain on the right ventricular muscle strips from normal and cardiomyopathic hamsters with alpha 1- and beta-adrenoceptor characteristics assessed by radioligand binding methods. At concentrations of 1.28, 2.56, 5.0 and 10 x 10 (-6) mol . litre (-1) noradrenaline raised isometric tension by 27 +/- 4, 39 +/- 5, 52 +/- 5 and 61 +/-6% in normal animals (n = 6). Corresponding increase of 65 +/- 8, 92 +/- 8, 109 +/- 9 and 115 +/- 10% occurred in cardiomyopathic hamsters (n=11, all P less than 0.02). The responses to isoprenaline (Emax =82%) and ouabain did not differ between the two groups of hamsters. [3H]-prazosin, a new radioligand, and [-3H]-dihydroalprenolol were used to assess alpha 1- and beta-adrenoceptors in cardiac membranes. By Scatchard analysis, the KD values for both ligands did not differ between normal and cardiomyopathic hamsters, but the maximum number of binding sites was higher in the myopathic group: 5.5 vs 3.9 fmol . mg [-1] protein for [3H]-prazosin and 27 vs 20 fmol . mg [-1] protein for [-3H]-dihydroalprenolol (both P less than 0.05). Histochemically, oxidative and glycolytic activity were normal but lysosomal acid phosphatase was high. Possible explanations for the raise response to noradrenaline in cardiomyopathic hamster include and increased concentration of noradrenaline in the synaptic cleft due to defective neuronal uptake and / or stimulation of an augmented population of alpha 1-(postsynaptic) adrenoceptors.
Animals↗
Chronic heart failure in the guinea pig increases cardiac alpha 1- and beta-adrenoceptors.
Compared with sham-operated guinea pigs, chronic heart failure produced by aortic constriction resulted in a 79% increase in alpha 1-adrenoceptor density as measured by [3H]prazosin binding (73 +/- 15 vs. 131 +/- 20 fmol/mg protein, P < 0.05); beta-adrenoceptor number, measured by (-)-[3H]dihydroalprenolol binding, increased by 93% (28 +/- 3.4 vs. 54 +/- 5.2 fmol/mg protein, P < 0.01). For each radioligand KD values were unchanged. Thus, congestive heart failure due to chronic pressure overload results in compensatory augmentation of alpha 1- and beta-adrenoceptor numbers.
Animals↗
Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol.
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Adult↗
A fluorescent analogue of propranolol does not label beta adrenoceptor sites.
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Aminacrine↗
Demonstration of alpha 1-adrenoceptors in guinea pig lung using 3H-prazosin.
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Animals↗
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.
Aged↗
Absorption of nicotine from small cigars.
The absorption of nicotine from cigars was measured in 7 male subjects who each smoked a single small cigar containing 14C-nicotine. The proportion of nicotine in the mainstream smoke delivered to the smoker's mouth was greater than that observed for cigarettes, but the proportion of nicotine in the cigar smoke which was retained by the smoker was about the same. The total dose of nicotine retained varied between 1 and 4.5 mg. Arterial plasma concentrations of nicotine were as high as those achieved by cigarette smoking but rose more slowly. Some nicotine from small cigars is absorbed by inhalation of the smoke into the lungs and some by buccal absorption.
Absorption↗