Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party.

To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death.Randomised, placebo controlled, single blind trial.226 general practices in the MRC general practice research framework.4396 patients aged 65-74 randomised to receive diuretic, beta blocker, or placebo. Patients had mean systolic pressures of 160-209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment.Patients were randomised to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily; or placebo. The regimens were adjusted to achieve specified target pressures. Mean follow up was 5.8 years.Strokes, coronary events, and deaths from all causes.Both treatments reduced blood pressure below the level in the placebo group. Compared with the placebo group, actively treated subjects (diuretic and beta blocker groups combined) had a 25% (95% confidence interval 3% to 42%) reduction in stroke (p = 0.04), 19% (-2% to 36%) reduction in coronary events (p = 0.08), and 17% (2% to 29%) reduction in all cardiovascular events (p = 0.03). After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke (31% (3% to 51%) p = 0.04), coronary events (44% (21% to 60%), p = 0.0009), and all cardiovascular events (35% (17% to 49%), p = 0.0005) compared with the placebo group. The beta blocker group showed no significant reductions in these end points. The reduction in strokes was mainly in non-smokers taking the diuretic.Hydrochlorothiazide and amiloride reduce the risk of stroke, coronary events, and all cardiovascular events in older hypertensive adults.     

Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure.

OBJECTIVE--To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure. DESIGN--Open randomised multicentre trial with three year follow up. SETTING--Outpatient departments of six French hospitals. PATIENTS--100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment). INTERVENTIONS--Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg. RESULTS--17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups. CONCLUSION--In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.     

Treatment of overt meningeal leukaemia in children: results of second MRC meningeal leukaemia trial.

After induction ofmeningeal remission by a course of intrathecal methotrexate patients were randomly allocated to receive either cranial irradiation or craniospinal irradiation. Patients being treated for their first meningeal relapse were randomised separately from those in their second or subsequent relapse. All eight patients in their first relapse who were given cranial irradiation alone developed further meningeal recurrence (median length of remission 15 weeks) compared with only two out of nine given craniospinal irradiation (median length of remission at least 99 weeks). Four of the nine patients given craniospinal irradiation were alive and without further meningeal relapse two and a half to four years after treatment. Craniospinal irradiation produced no such advantage for patients entering the trial in their second or subsequent meningeal relapse.     

Younger Age of Presentation and Extraosseous Tumour in IgD Myelomatosis

A study of 14 personal patients and 16 others in the literature shows that (1) IgD myelomatosis often presents at a significantly younger age than other forms of myelomatosis, and (2) during life extraosseous tumour can be detected in about two-thirds of these patients.The IgD form represents 1·5% of myelomatosis and shows an increased incidence of osteolytic lesions, hypercalcaemia, and renal failure, together with heavy Bence Jones proteinuria (90% type L).Like only Bence Jones myelomatosis, the IgD form seems to behave clinically in a more vicious manner.     

Urography in Myelomatosis

To investigate whether urographic contrast media might precipitate Bence Jones protein in the renal tubules and lead to renal failure in patients with myelomatosis, the reaction between the media and myeloma urine was studied in vitro. Appreciable precipitation was found only in urine at or below pH 4·5, and its occurrence did not correlate with the type or concentration of protein present. It is concluded that the risk of urography in myelomatosis is very small.     

The Kidney and Intravascular Coagulation in Myelomatosis

In 15 out of 35 patients with myelomatosis histological examination showed intravascular fibrin within the glomeruli, and this was associated with proliferation of the mesangial complex in 12. The presence of intravascular fibrin and mesangial proliferation was not associated with any specific immunoglobulin abnormality or with the presence or absence of Bence Jones proteinuria. In addition to fibrin being present within glomerular capillaries it was also shown in intertubular capillaries in three cases of myelomatosis with acute tubular necrosis. It is suggested that intraglomerular coagulation and fibrin deposition may contribute to the genesis of renal failure in myelomatosis.     

Controlled low protein diets in chronic renal insufficiency: meta-analysis.

OBJECTIVE--To determine whether low protein diets retard the development of end stage renal disease. DESIGN--Meta-analysis of 46 trials since 1975, from which six randomised controlled trials were selected. SETTING--Five trials in Europe and one in Australia between 1982 and 1991. SUBJECTS--890 patients with mild to severe chronic renal failure who were followed up for at least one year. 450 patients received a low protein diet and 440 a control diet. INTERVENTION--Difference in protein intake between control and treated groups of at least 0.2 g protein/kg/day. MAIN OUTCOME MEASURE--Number of renal deaths (the necessity to start dialysis or death of patient during study). RESULTS--156 renal deaths were recorded, 61 in the low protein diet group and 95 in the control group, leading to an odds ratio of low protein to control of 0.54 with a 95% confidence interval of 0.37 to 0.79. CONCLUSIONS--This result, obtained on a large population of patients suffering from chronic renal insufficiency, strongly supports the effectiveness of low protein diets in delaying the onset of end stage renal disease.     

Fast neutron treatment for squamous cell carcinoma of the head and neck: final report of Edinburgh randomised trial.

OBJECTIVE--To compare neutron treatment and megavoltage (photon) radiotherapy in locally advanced squamous cell carcinoma of the head and neck. DESIGN--Randomised trial of patients stratified by site of primary tumour and presence or absence of lymph node metastases. Follow up of patients after treatment. SETTING--Department of clinical oncology, Western General Hospital, Edinburgh. PATIENTS--165 Patients with untreated, histologically proved squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. All patients completed treatment, and no patient was lost to follow up. INTERVENTION--Treatment with either neutrons or photons. MAIN OUTCOME MEASURES--Disease state and morbidity (scored with the system of the European Organisation for Research on Treatment of Cancer) at each visit during follow up. RESULTS--Of the 165 patients, 85 were randomised to receive neutron treatment and 80 to receive photon treatment. Minimum follow up was five years. Local control of cancer remained similar in the two groups, being achieved in 37 (44%) patients after neutron treatment and 36 (45%) after photon treatment. Five year and actuarial 10 year survival rates were 24% (20/85) and 14% respectively in the group treated with neutrons and 34% (27/80) and 30% respectively in the group treated with photons. Five year survival rates without local disease were 19% (16/85) and 30% (24/80) respectively. Necrosis was more common after neutron treatment than after photon treatment. Seven patients in the neutron group who developed necrosis died whereas no deaths were associated with photon treatment. CONCLUSION--Rates of long term local control were similar in the two groups. Necrosis related to radiation was more common in patients treated with neutrons, and the mortality related to treatment was significantly higher in these patients.     

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.     

Myelomatosis: Comparison of Melphalan and Cyclophosphamide Therapy

Untreated patients suffering from myelomatosis were allocated at random for treatment by the daily oral administration of either cyclophosphamide or melphalan: 141 received cyclophosphamide and 133 melphalan. The trial began on 1 October 1964 and the intake of patients continued until 31 July 1968. The statistical analysis includes follow-up of the surviving patients to 31 May 1970.The most important single factor affecting the prognosis was the blood urea concentration at presentation. The median survival of the 125 patients whose blood urea concentration was less than 40 mg/100 ml was 33 months, compared with 20 months for the 96 patients whose blood urea concentration was 40-79 mg/100 ml and two months for the 55 patients whose blood urea concentration was 80 mg/100 ml or more.The median survival periods of the 114 patients in the cyclophosphamide group and of the 105 in the melphalan group whose blood urea concentration at presentation was less than 80 mg/100 ml were 27 and 23 months respectively. The difference is not statistically significant.     

Controlled trial of enalapril in patients with chronic fluid overload undergoing dialysis

About one third of patients receiving dialysis for end stage renal failure have chronic fluid overload despite advice to restrict their oral fluid intake. To investigate the potential of an angiotensin converting enzyme inhibitor in reducing the urge to drink and consequent gain in weight, a double blind, placebo controlled crossover trial of enalapril was conducted in 25 patients receiving dialysis who had fluid overload. The trial comprised a baseline period of four weeks; two periods of treatment, each of four weeks, during which patients received either placebo or enalapril 5 mg twice each week; and a follow up period of four weeks. Five patients withdrew from the trial, one because of an adverse drug reaction to enalapril. A range of biochemical and behavioural variables was measured during the baseline period, at the completion of periods 1 and 2, and during follow up. These variables included gain in weight between dialysis sessions; blood pressure; plasma concentrations of sodium, angiotensin II, and vasopressin; plasma renin and angiotensin converting enzyme activities; osmolality; and estimations of thirst, intake of fluid, and control of drinking. Enalapril caused a significant reduction in gain in weight between dialysis sessions, thirst, and oral intake of fluid in parallel with significantly increased renin activity, significantly decreased angiotensin converting enzyme activity, and decreased concentrations of angiotensin II. Gain in weight and angiotensin converting enzyme activity returned to baseline values once patients stopped taking enalapril.These results suggest that enalapril may act on the renin-angiotensin system and reduce intake of fluid by inhibiting angiotensin converting enzyme.     

Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial.

OBJECTIVE--To evaluate the acceptability and efficacy of adding cognitive behaviour therapy to the medical care of patients presenting with the chronic fatigue syndrome. DESIGN--Randomised controlled trial with final assessment at 12 months. SETTING--An infectious diseases outpatient clinic. SUBJECTS--60 consecutively referred patients meeting consensus criteria for the chronic fatigue syndrome. INTERVENTIONS--Medical care comprised assessment, advice, and follow up in general practice. Patients who received cognitive behaviour therapy were offered 16 individual weekly sessions in addition to their medical care. MAIN OUTCOME MEASURES--The proportions of patients (a) who achieved normal daily functioning (Karnofsky score 80 or more) and (b) who achieved a clinically significant improvement in functioning (change in Karnofsky score 10 points or more) by 12 months after randomisation. RESULTS--Only two eligible patients refused to participate. All randomised patients completed treatment. An intention to treat analysis showed that 73% (22/30) of recipients of cognitive behaviour therapy achieved a satisfactory outcome as compared with 27% (8/30) of patients who were given only medical care (difference 47 percentage points; 95% confidence interval 24 to 69). Similar differences were observed in subsidiary outcome measures. The improvement in disability among patients given cognitive behaviour therapy continued after completion of therapy. Illness beliefs and coping behaviour previously associated with a poor outcome changed more with cognitive behaviour therapy than with medical care alone. CONCLUSION--Adding cognitive behaviour therapy to the medical care of patients with the chronic fatigue syndrome is acceptable to patients and leads to a sustained reduction in functional impairment.     

Causes of treatment failure and death in carcinoma of the lung

Studies of patterns of failure and causes of death have been undertaken based upon the WHO histopathologic classification. In a randomized trial of thoracic irradiation +/- chemotherapy (hydroxyurea and CCNU), patterns of failure did not seem to differ by cell type; the largest group was "death without progression." A subsequent clinical trial of thoracic irradiation +/- cranial irradiation permitted a more detailed evaluation. Patients with squamous cell carcinoma had a higher rate of local failure than distant metastasis. Those with small cell carcinoma had a lower local failure rate and a high rate of distant spread. Patients with adenocarcinoma and large cell carcinoma had the lowest local failure rate, but had a high rate of distant metastasis. In 300 consecutive patients with autopsies, 75 percent with squamous carcinoma died of complications of the thoracic tumor and only one-quarter had extrathoracic dissemination; 30 percent with small cell carcinoma died of local tumor complications and 70 percent had carcinomatosis; 40 percent of patients with adenocarcinoma and large cell carcinoma died of intrathoracic complications, and 55 percent had distant metastases. Half the patients with small cell carcinoma, large cell carcinoma, and adenocarcinoma had brain metastases at autopsy. Future clinical trials should emphasize better control of the most common sites of failure.     

MRC OX-2 antigen: a lymphoid/neuronal membrane glycoprotein with a structure like a single immunoglobulin light chain.

The MRC OX-2 antigen is a rat cell surface glycoprotein of mol. wt. 41 000-47 000 found on neurones, thymocytes, B cells, follicular dendritic cells and endothelium. We now report the amino sequence for this antigen as deduced from the nucleotide sequence of cDNA clones detected by use of an oligonucleotide probe. The sequence contains 248 amino acid residues of which 202 residues are likely to be outside the cell with two domains that show homology with immunoglobulins. The N-terminal domain fits best with Ig V domains and Thy-1 antigen while the C-terminal part is like an Ig C domain. Thus the structure overall is similar to an Ig light chain or the T cell receptor beta chain. Three glycosylation sites are identified on each of the MRC OX-2 antigen domains.     

Does hospital at home for palliative care facilitate death at home? Randomised controlled trial

ObjectiveTo evaluate the impact on place of death of a hospital at home service for palliative care.DesignPragmatic randomised controlled trial.SettingFormer Cambridge health district.Participants229 patients referred to the hospital at home service; 43 randomised to control group (standard care), 186 randomised to hospital at home.InterventionHospital at home versus standard care.ResultsTwenty five (58%) control patients died at home compared with 124 (67%) patients allocated to hospital at home. This difference was not significant; intention to treat analysis did not show that hospital at home increased the number of deaths at home. Seventy three patients randomised to hospital at home were not admitted to the service. Patients admitted to hospital at home were significantly more likely to die at home (88/113; 78%) than control patients. It is not possible to determine whether this was due to hospital at home itself or other characteristics of the patients admitted to the service. The study attained less statistical power than initially planned.ConclusionIn a locality with good provision of standard community care we could not show that hospital at home allowed more patients to die at home, although neither does the study refute this. Problems relating to recruitment, attrition, and the vulnerability of the patient group make randomised controlled trials in palliative care difficult. While these difficulties have to be recognised they are not insurmountable with the appropriate resourcing and setting.

Key messages

• Terminally ill patients allocated to hospital at home were no more likely to die at home than patients receiving standard care
• Although the subsample of patients actually admitted to hospital at home did show a significant increase in likelihood of dying at home, whether this was due to the service itself or the characteristics of patients admitted to hospital at home could not be determined
• The need to balance ideal research design against the realities of evaluation of palliative care had the effect that the trial achieved less statistical power than originally planned
• Particular problems were that many patients failed to receive the allocated intervention because of the unpredictable nature of terminal illness, inclusion of other service input alongside hospital at home, and the wide range of standard care available
• The trial illustrated problems associated with randomised controlled trials in palliative care, none of which are insurmountable but which require careful consideration and resourcing before future trials are planned

     

Prevalence of advanced renal failure in Northern Ireland.

OBJECTIVE--To determine the prevalence of advanced chronic renal failure in Northern Ireland as part of an assessment by the Renal Association of the level of service provision for treatment of such patients. DESIGN--Prospective notification of patients reaching a defined level of advanced chronic renal failure (serum creatinine concentration greater than or equal to 500 mumol/l or blood urea concentration greater than or equal to 25 mmol/l) within one year and follow up for at least three, and, at most, four years after notification. SETTING--Northern Ireland. PATIENTS--122 Patients with a serum creatinine or blood urea concentration higher than the defined level newly detected from 1 March 1985 to 28 February 1986. MAIN OUTCOME MEASURE--Survival after notification. RESULTS--77 Patients of all ages/million population/year had advanced chronic renal failure compared with 67/million/year between the ages of 5 and 80 found in an earlier study of the same population. 62% Of the patients were older than 50 years. Seventeen (14%) of the patients either required dialysis or died within one month of notification, 51 (42%) survived for at least three months, and 23 (19%) for one year or longer. Three patients, all of whom were attending a renal clinic, survived for periods of 43, 45, and 46 months respectively without renal replacement treatment. CONCLUSIONS--The increased number of new patients disclosed in this survey compared with the earlier survey is mainly owing to an increased number of older patients. Such patients often have disabilities other than renal failure, are less likely to be capable of self treatment, may develop complications more often and require more frequent hospital admissions, and may not be suitable for transplantation and consequently have considerable resource implications for the NHS.     

Controlled trial of psychiatric nurse therapists in primary care.

In a randomised controlled clinical trial neurotic patients (mainly phobic and obsessive-compulsive) did significantly better up to one year follow up after receiving behavioural psychotherapy from a nurse therapist rather than routine treatment from a general practitioner. At the end of the year control patients who had not improved had crossover behavioural treatment from the nurse and then improved. Those who dropped out or refused therapy did not show worthwhile gains. Patients preferred being treated in the primary care setting rather than in hospital. Placing nurse therapists in primary care is not only viable but may save more health care resources than it consumes.     

Continuous ambulatory peritoneal dialysis: one year's experience in a UK dialysis unit.

Thirty-two patients aged 8-63 years trained to manage themselves by continuous ambulatory peritoneal dialysis for end-stage renal failure achieved better steady-state serum biochemistry and much higher haemoglobin and lower serum phosphate concentrations than during treatment with haemodialysis up to one year before. Two patients, however, returned to intermittent haemodialysis because of recurrent peritonitis. Costs of the technique during the first year were less than half those incurred in the first year of home haemodialysis. Nevertheless, the major advantage was the ease with which patient independence and rehabilitation could be achieved. This technique is an appreciable advance over other forms of management for end-stage renal failure. Nevertheless, until it is more refined and long-term problems have been assessed it should probably be used only in established renal units where back-up treatments are available.     

Sodium restriction and blood pressure in hypertensive type II diabetics: randomised blind controlled and crossover studies of moderate sodium restriction and sodium supplementation.

OBJECTIVE--To determine the effect of moderate dietary sodium restriction on the hypertension of non-insulin-dependent (type II) diabetes. DESIGN--Randomised parallel controlled study of moderate sodium restriction for three months compared with usual diabetic diet, followed by randomised double blind crossover trial of sustained release preparation of sodium for one month versus placebo for one month in patients continuing with sodium restriction. SETTING--Patients attending diabetic outpatient clinic of city hospital. PATIENTS--Thirty four patients with established type II diabetes complicated by mild hypertension (systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 95 mm Hg on three consecutive occasions). Patients already taking antihypertensive agents (but not diuretics) not barred from study provided that criteria for mild hypertension still met. Conditions precluding patients from study were diabetic or hypertensive nephropathy, cardiac failure, and pregnancy. INTERVENTIONS--After run in phase with recordings at seven weeks, three weeks, and time zero patients were allocated at random to receive moderate dietary sodium restriction for three months (n = 17) or to continue with usual diabetic diet. Subsequently nine patients in sodium restriction group continued with regimen for a further two months, during which they completed a randomised double blind crossover trial of sustained release preparation of sodium (Slow Sodium 80 mmol daily) for one month versus matching placebo for one month. END POINT--Reduction in blood pressure in type II diabetics with mild hypertension. MEASUREMENTS AND MAIN RESULTS--Supine and erect blood pressure, body weight, and 24 hour urinary sodium and potassium excretion measured monthly during parallel group and double blind crossover studies. After parallel group study sodium restriction group showed significant reduction in systolic blood pressure (supine 19.2 mm Hg, erect 21.4 mm Hg; p less than 0.001) and mean daily urinary sodium excretion (mean reduction 60 mmol/24 h). There were no appreciable changes in weight, diabetic control, or diastolic pressure. No significant changes occurred in controls. In double blind crossover study mean supine systolic blood pressure rose significantly (p less than 0.005) during sodium supplementation (to 171 mm Hg) compared with value after three months of sodium restriction alone (159.9 mm Hg) and after one month of placebo (161.8 mm Hg). CONCLUSIONS--Moderate dietary restriction of sodium has a definite hypotensive effect, which may be useful in mild hypertension of type II diabetes.     

Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. The Scottish Breast Cancer Committee.

OBJECTIVE--To investigate the incidence of fatal myocardial infarction in women in the two randomised arms of the Scottish adjuvant tamoxifen trial. DESIGN--Retrospective review of hospital notes to determine with the greatest possible certainty women who had died of an acute myocardial infarction. SETTING--Scottish Cancer Trials Office, the University of Edinburgh. PATIENTS--1070 postmenopausal women with operable breast cancer who were randomised to receive either adjuvant tamoxifen for five years or until relapse (539 patients) or tamoxifen for at least six weeks on the confirmation of first recurrence (531 patients). MAIN OUTCOME MEASURES--Incidence of fatal myocardial infarction in women with no known or suspected systemic cancer. RESULTS--Of the 200 women who died in the adjuvant tamoxifen arm of the trial, 44 were free of cancer at death and 10 of these died of myocardial infarction. In the observation arm 251 women died, of whom 61 showed no evidence of systemic cancer and 25 had a fatal myocardial infarction. The incidence of fatal myocardial infarction in the two groups was significantly different (chi 2 = 6.88, p = 0.0087). CONCLUSION--Tamoxifen given for at least five years as adjuvant therapy for breast cancer seems to have a cardioprotective oestrogen-like effect in postmenopausal women.