The Women's international study of long-duration oestrogen after menopause (WISDOM): a randomised controlled trial

BACKGROUND: At the time of feasibility work and final design of the trial there was no randomised control trial evidence for the long-term risks and benefits of hormone replacement therapy. Observational studies had suggested that long term use of estrogen was likely to be associated, amongst other things, with reduced risks of osteoporosis and ischaemic heart disease and increased risks of breast and endometrial cancer. Concomitant use of progestogens had been shown to protect against endometrial cancer, but there were few data showing how progestogen might affect estrogen actions on other conditions. Disease specific risks from observational studies suggested that, overall, long-term HRT was likely to be beneficial. Several studies showed that mortality from all causes was lower in HRT users than in non-users. Some secondary cardiovascular prevention trials were ongoing but evidence was also required for a range of outcomes in healthy women. The WISDOM trial was designed to compare combined estrogen and progestogen versus placebo, and estrogen alone versus combined estrogen and progestogen. During the development of WISDOM the Women's Health Initiative trial was designed, funded and started in the US. DESIGN: Randomised, placebo, controlled, trial. METHODS: The trial was set in general practices in the UK (384), Australia (94), and New Zealand (24). In these practices 284175 women aged 50–69 years were registered with 226282 potentially eligible. We sought to randomise 22300 postmenopausal women aged 50 – 69 and treat for ten years. The interventions were: conjugated equine estrogens, 0.625 mg orally daily; conjugated equine estrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily; matched placebo. Primary outcome measures were: major cardiovascular disease, osteoporotic fractures, breast cancer and dementia. Secondary outcomes were: other cancers, all cause death, venous thromboembolism and cerebro-vascular disease. RESULTS: The trial was prematurely closed during recruitment following publication of early results from the Women's Health Initiative. At the time of closure, 56583 had been screened, 8980 entered run-in, and 5694 (26% of target of 22,300) randomised. Those women randomised had received a mean of one year of therapy, mean age was 62.8 years and total follow-up time was 6491 person years. DISCUSSION: The WISDOM experience leads to some simple messages. The larger a trial is the more simple it needs to be to ensure cost effective and timely delivery. When a trial is very costly and beyond the resources of one country, funders and investigators should make every effort to develop international collaboration with joint funding

The management of newly identified asthma in primary care in England.

Aims: To establish by case note review how people with newly diagnosed asthma were treated in general practice. Methods: A retrospective cross-sectional survey was carried out in twelve general practices from the MRC General Practice Research Framework. Children between their 3rd and 8th birthdays and adults 16 years and over were identified with newly diagnosed or treated asthma from computer records with further details obtained from a case record search. The main outcome measure was the time of recorded asthma diagnosis and the time of first prescriptions for inhaled corticosteroids. Results: For 41% of children and 53% of adults with a diagnosis of asthma and inhaled corticosteroids, inhaled corticosteroids were prescribed before or on the same day as the diagnosis of asthma was recorded. Diagnosis tended to be made on the basis of a patient's medical history with fewer than 20% of patients having results of any tests recorded in their medical notes. The time from first respiratory consultation to inhaled corticosteroid prescription was statistically significantly shorter in those children for whom a diagnosis of asthma was recorded (p=0.038) compared to those children without a recorded diagnosis of asthma. Conclusions: Inhaled corticosteroids are frequently prescribed before a diagnosis of asthma is recorded. A diagnostic label of asthma in children significantly reduces the length of time from the date of first respiratory consultation to inhaled corticosteroid prescription. If inhaled corticosteroids are to be prescribed early there must be an improvement in the diagnosis of asthma in primary care, including the recording of results in patient's medical notes

Health related quality of life after combined hormone replacement therapy: randomised controlled trial

Objective: To assess the effect of combined hormone replacement therapy (HRT) on health related quality of life. Design: Randomised placebo controlled double blind trial. Setting: General practices in United Kingdom (384), Australia (94), and New Zealand (24). Participants Postmenopausal women aged 50-69 at randomisation; 3721 women with a uterus were randomised to combined oestrogen and progestogen (n=1862) or placebo (n=1859). Data on health related quality of life at one year were available from 1043 and 1087women, respectively. Interventions: Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year. Main outcome measures: Health related quality of life and psychological wellbeing as measured by the women’s health questionnaire. Changes in emotional and physical menopausal symptoms as measured by a symptoms questionnaire and depression by the Centre for Epidemiologic Studies depression scale (CES-D). Overall health related quality of life and overall quality of life as measured by the European quality of life instrument (EuroQol) and visual analogue scale, respectively. Results: After one year small but significant improvements were observed in three of nine components of the women’s health questionnaire for those taking combined HRT compared with those taking placebo: vasomotor symptoms (P<0.001), sexual functioning (P<0.001), and sleep problems (P<0.001). Significantly fewer women in the combined HRT group reported hot flushes (P<0.001), night sweats (P<0.001), aching joints and muscles (P=0.001), insomnia (P<0.001), and vaginal dryness (P<0.001) than in the placebo group, but greater proportions reported breast tenderness (P<0.001) or vaginal discharge (P<0.001). Hot flushes were experienced in the combined HRT and placebo groups by 30% and 29% at trial entry and 9% and 25% at one year, respectively. No significant differences in other menopausal symptoms, depression, or overall quality of life were observed at one year. Conclusions: Combined HRT started many years after the menopause can improve health related quality of life.Amanda J Welton, Madge R Vickers, Joseph Kim, Deborah Ford, Beverley A Lawton, Alastair H MacLennan, Sarah K Meredith, Jeannett Martin and Tom W Meade for the WISDOM tea

Population-based multidimensional assessment of older people in UK general practice: a cluster-randomised factorial trial

BACKGROUND: The benefit of multidimensional assessment and management of older people remains controversial. Most trials have been too small to produce adequate evidence to inform policy. We aimed to measure the effects of different approaches to assessment and management of older people. METHODS: We undertook a cluster-randomised factorial trial in 106 general practices (43219 eligible patients aged 75 years and older, 78% participation), comparing (1) universal versus targeted assessment and (2) subsequent management by hospital outpatient geriatric team versus the primary-care team. All participants received a brief multidimensional assessment followed by a nurse-led in-depth assessment in the universal group, whereas in the targeted group the in-depth assessment was offered only to those with problems established at the brief assessment. Referrals to the randomised team (geriatric management or primary care), other medical or social services, health-care workers, or agencies, and emergency referrals to the general practitioner were based on a standard protocol at the in-depth assessment. The primary endpoints were mortality, admissions to hospital and institution, and quality of life. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standardised Randomised Controlled Trial Number ISRCTN23494848. FINDINGS: Mortality and hospital or institutional admissions did not differ between groups. During 3 years' follow-up, significant improvements in quality of life resulted from universal versus targeted assessment in terms of homecare, and from management by geriatric team versus primary-care team, in terms of mobility, social interaction, and morale. However, only the result for social interaction was consistent with a small but important effect. INTERPRETATION: The different forms of multidimensional assessment offered almost no differences in patient outcome